Total Body Clearance (total + body_clearance)

Distribution by Scientific Domains


Selected Abstracts


Comparative disposition of ricobendazole enantiomers after intravenous and subcutaneous administration of a racemic formulation to calves

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2000
Carles Cristfol
Abstract The enantioselective disposition kinetics of the benzimidazole anthelmintic, ricobendazole (RBZ), have been characterized after its intravenous (iv) and subcutaneous (sc) administration as a racemic formulation to cattle. The (+) and (,) RBZ enantiomeric forms were recovered in plasma after iv and sc administration of the racemic RBZ formulation, using a chiral phase based HPLC method. A biexponential plasma concentration versus time curve was observed for both RBZ enantiomers following the iv treatment. Total body clearance was higher for (,) RBZ (150.4 mL/h,,kg) compared with that obtained for the (+) RBZ antipode (78.1 mL/h,,kg). The elimination half-life of the (,) RBZ enantiomer was shorter (T1/2,: 2.67 h) compared with the (+) enantiomer (T1/2,: 5.41 h). The plasma availability (expressed as AUC) was significantly higher for (+) RBZ compared with that obtained for the (,) antipode following both treatments. The enantiomeric ratio in plasma at T0 was close to unity (50% of each enantiomer); the analysis of the concentration ratios (+) RBZ/(,) RBZ, demonstrated an increase in the proportion of (+) RBZ during the time course of the kinetics after both iv and sc treatments. The results presented herein show the enantioselective disposition kinetics of RBZ in cattle and are a further contribution to the understanding of the kinetic behaviour of these sulphoxide-containing benzimidazole anthelmintics in ruminants. Copyright 2000 John Wiley & Sons, Ltd. [source]


Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

INTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2001
Shigeru Satoh
Abstract Background: The circadian variation of clinical pharmacokinetics of tacrolimus in kidney transplant recipients receiving continuous intravenous administration has not been clarified. The aim of this study was to evaluate the circadian variation of this drug in continuous intravenous administration, with regard to the dosing scheme for conversion from intravenous to oral therapy. Methods: The blood concentration,time curve was studied in 10 living-related kidney transplant recipients, aged 18,51 years (mean, 36.5 years), 1 day before operation for preoperative oral administration, the third postoperative day for continuous intravenous administration and the sixth postoperative day at the conversion from intravenous to oral therapy. Results: Although the total body clearance of daytime was slightly higher than that of night-time, the intravenous tacrolimus infusion maintained an adequate therapeutic blood concentration for 24 h. There were significant differences between the preoperative and the postoperative state in the area under the curve, total body clearance and bioavailability for the oral administration. The mean absolute bioavailability was 17.7% in preoperative and 11.1% in postoperative state, respectively and a large interindividual variation was confirmed in this parameter, which was 7.0,27.2% for preoperative and 6.4,22.0% for postoperative area under the curve, respectively. Conclusion: This study proposes that intravenous administration is a safe and appropriate method to achieve the required blood concentration in patients with various tacrolimus metabolism in the early post-transplant period. As the oral tacrolimus absorption was found to be variable between preoperative and postoperative states in identical patients, the conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics. Frequent blood concentration monitoring is needed to ensure safe treatment. [source]


Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2009
H. Fukuchi MS
Summary Objective:, To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (nonmem) in Japanese patients treated with oral therapy. Method:, Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. Results:, Estimates generated using nonmem indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 016 TBW 053AGE , 65 078BMI , 25 DD051, Vd (L) = 102 TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) ,65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m2) ,25 = 1 for patient was 25 kg/m2 or over and 0 otherwise and Vd is apparent volume of distribution. The clearance of AMD decreased significantly by 223% with a BMI higher than 25 kg/m2. The clearance of AMD also decreased significantly by 469% when patient age was more than 65 years. Conclusion:, Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD. [source]


Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patients

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2005
E. Yukawa PhD
Summary Objective:, To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. Method:, A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. Results:, The final pharmacokinetic model was Cl (L/h) = 375TBW0567AGE,0374Conc,0719148DOSE , 5, Vd (L/kg) = 413 and ka (h,1) = 0363, where Cl is total body clearance, Vd is apparent volume of distribution, ka is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (,g/mL), and DOSE , 5 = 1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. Conclusion:, Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect. [source]


Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2003
E. Yukawa
Summary Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam,valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 03,326 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 1440 TBW,0172 114VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 172 TBW,0264 DOSE0159 0821CZP 0896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 179% decrease in valproic acid clearance. [source]


Effect of temperature on pharmacokinetics of enrofloxacin in mud crab, Scylla serrata (Forsskl), following oral administration

JOURNAL OF FISH DISEASES, Issue 3 2008
W H Fang
Abstract The study was conducted to evaluate the pharmacokinetics of enrofloxacin following a single oral gavage (10 mg kg,1) in mud crab, Scylla serrata, at water temperatures of 19 and 26 C. Enrofloxacin concentration in haemolymph was determined using high-performance liquid chromatography (HPLC). A multiple and repeated haemolymph sampling from the articular cavity of crab periopods was developed. The haemolymph of an individual crab was successfully sampled up to 11 times from the articular cavity. The profile of haemolymph enrofloxacin concentration of an individual crab versus time was thus achieved. The mean haemolymph enrofloxacin concentration versus time was described by a two-compartment model with first-order absorption at two water temperatures. The peak concentrations of haemolymph enrofloxacin at 19 and 26 C were 7.26 and 11.03 ,g mL,1, at 6 and 2 h, respectively. The absorption and distribution half-life time ( and t1/2,) at 19 C were 3.7 and 4.5 h, respectively, which were markedly larger than the corresponding values (1.1 and 1.5 h) at 26 C; the elimination half-life time (t1/2,) was 79.1 and 56.5 h at 19 and 26 C, respectively. The area under curve (AUC), total body clearance (Cl) and mean residence time (MRT0,,) at 19 C were 636.0 mg L,1 h, 0.016 L h,1 kg,1 and 102.5 h, respectively; the corresponding values at 26 C were 583.4 mg L,1 h, 0.018 L h,1 kg,1and 63.7 h. These results indicate that enrofloxacin is absorbed and eliminated more rapidly in mud crab at 26 C than at 19 C. [source]


Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2010
G. SELLERS
Sellers, G., Lin, H. C., G. Riddell, M. G., Ravis, W. R., Lin, Y. J., Duran, S. H., Givens, M.D. Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. J. vet. Pharmacol. Therap. 33, 480,484. The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma Tmax was 0.083 h and plasma Cmax was 18 135 22 720 ng/mL. Plasma AUC was 4484 1,398 ngh/mL. Plasma t, was 1.80 0.50 h and mean residence time was 0.794 0.318 h with total body clearance of 1.29 0.70 L/h/kg. The mean plasma steady-state volume of distribution was calculated as 0.990 0.530 L/kg and volume of distribution based on area was calculated as 3.23 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 11.8 ng/mL. Milk Tmax was detected at 0.67 0.26 h with Cmax of 2495 904 ng/mL. Milk AUC till the last time was 6593 2617 ngh/mL with mean AUC milk to AUC plasma ratio of 1.99 2.15. The last measurable time that ketamine was detected in milk was 44 10.0 h with a mean concentration of 16.0 9.0 ng/mL. [source]


Characterization of the pharmacokinetic disposition of levofloxacin in stallions after intravenous and intramuscular administration

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2008
A. GOUDAH
The target of the present study was to investigate the plasma disposition kinetics of levofloxacin in stallions (n = 6) following a single intravenous (i.v.) bolus or intramuscular (i.m.) injection at a dose rate of 4 mg/kg bwt, using a two-phase crossover design with 15 days as an interval period. Plasma samples were collected at appropriate times during a 48-h administration interval, and were analyzed using a microbiological assay method. The plasma levofloxacin disposition was best fitted to a two-compartment open model after i.v. dosing. The half-lives of distribution and elimination were 0.21 0.13 and 2.58 0.51 h, respectively. The volume of distribution at steady-state was 0.81 0.26 L/kg, the total body clearance (Cltot) was 0.21 0.18 L/h/kg, and the areas under the concentration,time curves (AUCs) were 18.79 4.57 ,g.h/mL. Following i.m. administration, the mean t1/2el and AUC values were 2.94 0.78 h and 17.21 4.36 ,g.h/mL. The bioavailability was high (91.76% 12.68%), with a peak plasma mean concentration (Cmax) of 2.85 0.89 ,g/mL attained at 1.56 0.71 h (Tmax). The in vitro protein binding percentage was 27.84%. Calculation of efficacy predictors showed that levofloxacin might have a good therapeutic profile against Gram-negative and Gram-positive bacteria, with an MIC , 0.1 ,g/mL. [source]


Allometric basis of enrofloxacin scaling in green iguanas

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2008
L. K. MAXWELL
When body size varies greatly, drug disposition can best be described as an allometric function of body weight. Therefore, the allometry of standard metabolic rate (SMR; 3/4 power) and body surface area (BSA; 2/3 power) have been advocated as surrogate markers for the prediction of key pharmacokinetic parameters. The goal of the present study was to examine the allometric basis of pharmacokinetic scaling within a species, green iguanas. Enrofloxacin was administered intravenously to 20 green iguanas (322,3824 g), and noncompartmental analysis was used to calculate standard pharmacokinetic parameters, which were log10 transformed and regressed against log10 body weight. The slopes of significant regressions were compared with the values of unity, 3/4, and 2/3. The slope of enrofloxacin total body clearance (Cl) was also compared with the slopes relating SMR and renal Cl of 99mTc-diethylenetriamine penta-acetic acid (99mDTPA) to body weight in iguanas. Enrofloxacin Cl depended allometrically on body weight with the power of 0.32. The slope of enrofloxacin Cl was significantly less than those of SMR, Cl of 99mDTPA, and the 2/3 value. Therefore, the relationship between enrofloxacin Cl and body weight does not directly depend on the allometry of BSA, SMR, or renal Cl of 99mDTPA in iguanas. [source]


Pharmacokinetic,pharmacodynamic integration of orbifloxacin in rabbits after intravenous, subcutaneous and intramuscular administration

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2008
P. MARN
The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits (n = 6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration,time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution (Vss) and total body clearance (Cl) of orbifloxacin after i.v. administration were estimated to be 1.71 0.38 L/kg and 0.91 0.20 L/hkg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95 0.82 and 3.24 1.33 mg/L at 0.67 0.20 and 0.65 0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67 11.02% and 109.87 8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC/MIC and Cmax/MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations. [source]


Pharmacokinetics of cefepime administered by i.v. and i.m. routes to ewes

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2005
M. ISMAIL
The pharmacokinetics of cefepime were studied following i.v. and i.m. administration of 20 mg/kg in 10 ewes. Following i.v. administration of a single dose, the plasma concentration,time curves of cefepime were best fitted using a two-compartment open model. The elimination half-life (t1/2,) was 1.76 0.07 h, volume of distribution at steady-state [Vd(ss)] was 0.32 0.01 L/kg and total body clearance (ClB) was 2.37 0.05 mL/minkg. Following i.m. administration, the drug was rapidly absorbed with an absorption half-life (t1/2ab) of 0.49 0.05 h, maximum plasma concentration (Cmax) of 31.9 1.5 ,g/mL was attained at (tmax) 1.1 0.2 h and the drug was eliminated with an elimination half-life (t1/2el) of 2.06 0.11 h. The systemic bioavailability (F) after i.m. administration of cefepime was 86.8 7.5%. The extent of plasma protein binding measured in vitro was 14.8 0.54%. The drug was detected in urine for 36 h postadministration by both routes. [source]


Bioavailability and pharmacokinetics of florfenicol in broiler chickens

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2003
J. Shen
The bioavailability and pharmacokinetic disposition of florfenicol in broiler chickens were investigated after intravenous (i.v.), intramuscular (i.m.) and oral administrations of 15 and 30 mg/kg body weight (b.w.). Plasma concentrations of florfenicol were determined by a high performance liquid chromatographic method in which plasma samples were spiked with chloramphenicol as internal standard. Plasma concentration,time data after i.v. administration were best described by a two-compartment open model. The elimination half-lives were 168 43 and 181 71 min, total body clearance 1.02 0.17 and 1.02 0.16 Lkg/h, the volume of distribution at steady-state 4.99 1.11 and 3.50 1.01 L/kg after i.v. injections of 15 and 30 mg/kg b.w., respectively. Plasma concentration,time data after i.m. and oral administrations were adequately described by a one-compartment model. The i.m. bioavailability and the oral bioavailability of florfenicol were 95, 98 and 96, 94%, respectively, indicating that florfenicol was almost absorbed completely after i.m. and oral administrations of 15 and 30 mg/kg b.w. [source]


Pharmacokinetics and pharmacodynamics of clemastine in healthy horses

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2003
K. Trneke
Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 ,g/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 ,g/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations. [source]


Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogs

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2002
M. COULET
The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (tmax) 1.5 h], reaching a mean maximum concentration (Cmax) of 6 ,g/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (Vss) and Varea of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both Cmax and area under the concentration,time curve (AUC) showed dose proportionality over the dose range tested (7.5,30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing Cmax and AUC, but did not change tmax. High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9,99.9% of the dose within 48 h. [source]


Effects of altered plasma ,-1-acid glycoprotein levels on pharmacokinetics of some basic antibiotics in pigs: simulation analysis

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2001
M. Kuroha
Effects of altered plasma , -1-acid glycoprotein (AGP) levels on pharmacokinetic parameters of basic antimicrobials, erythromycin (EM), lincomycin (LM) and clindamycin (CM) were evaluated in pigs by simulation analysis. Intravenous (i.v.) injections of EM, LM and CM were performed to obtain pharmacokinetic parameters in healthy conditions. Binding parameters were obtained from an in vitro study using ultrafiltration. Simulation studies indicated that an increase of plasma AGP levels resulted in a decrease of both volume of distribution at steady state (Vdss) and total body clearance (Cltot) for all the drugs. Elimination rate constant for LM was almost unchanged by an increase of plasma AGP levels, whereas those for EM and CM were increased. Plasma concentration,time profiles at a high AGP level (often observed in pathophysiological conditions) were also simulated. All of the total plasma concentration,time profiles were different from those at normal AGP level. The differences were characterized by a higher initial concentration with faster or similar elimination. Unbound plasma concentration,time profile of LM was unaffected by AGP levels, whereas EM and CM were eliminated from plasma more rapidly at high AGP level. These results suggested that adjustment of dosage regimen of EM and CM is required in pathophysiological conditions, but that of LM is not required. [source]


Bioavailability of amprolium in fasting and nonfasting chickens after intravenous and oral administration

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2000
Hamamoto
The bioavailability of amprolium (APL) was measured after intravenous (i.v.) and oral (p.o.) administration to chickens. Twelve healthy chickens weighing 1.28,1.41 kg received a dose of 13 mg APL/kg intravenously, and 13 or 26 mg APL/kg orally in both a fasted and a nonfasted condition in a Latin square design. Plasma samples were taken from the subwing vein for determination of APL concentration by HPLC method. The data following intravenous and oral administration were best fitted by 2-compartment and 1-compartment models, respectively, using weighted nonlinear least squares regression. The half-life beta t,, volume of distribution (Vd) and total body clearance (Cl) after intravenous administration were 0.21 h, 0.12 L/kg and 1.32 L/h.kg, respectively. The elimination half-life (t Kel) after oral administration was 0.292,0.654 h which is 1.5,3.2 times longer than after intravenous administration, suggesting the presence of a ,flip-flop' phenomenon in chickens. The maximum plasma concentration (Cmax) of 13 mg/kg APL administered orally to chickens during fasting was significantly (about four times) higher than that during nonfasting (P < 0.05). Bioavailability during nonfasting was from 2.3 to 2.6%, and 6.4% during fasting. [source]


Simultaneous determination of amantadine and rimantadine by HPLC in rat plasma with pre-column derivatization and fluorescence detection for pharmacokinetic studies

BIOMEDICAL CHROMATOGRAPHY, Issue 9 2005
Yasuhiko Higashi
Abstract We investigated simultaneous high-performance liquid chromatographic (HPLC) determination of amantadine hydrochloride (AMA) and rimantadine hydrochloride (RIM) levels in rat plasma after fluorescent derivatization with o -phthalaldehyde and 2-mercaptoethanol. Afterwards, the method was applied to determine their pharmacokinetics. The retention times of AMA and RIM derivatives were 12.6 and 22.2 min and the lower limits of detection were 0.025 and 0.016 g[sol ]mL, respectively. The coefficients of variation for intra- and inter-day assay of AMA and RIM were less than 5.1 and 7.6%, respectively. After i.v. administration of AMA or RIM to rats, the total body clearance and distribution volume at the steady-state of RIM were higher than those of AMA. Bioavailability of AMA and RIM was 34.9 and 37.2%, respectively. When AMA and RIM were p.o. co-administered, the area under the plasma concentration,time curve of RIM was significantly lower than that after RIM alone. On the other hand, pharmacokinetic parameters of AMA did not significantly change. These results indicate that our HPLC assay is simple, rapid, sensitive and reproducible for simultaneously determining AMA and RIM concentrations in rat plasma and is applicable to their pharmacokinetic studies. Also, co-administration of AMA and RIM may result in the lack of pharmacological effects of RIM. Copyright 2005 John Wiley & Sons, Ltd. [source]


Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2009
Ju-Hee Oh
Abstract The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization compared with conscious rats. These results demonstrate that the pharmacokinetics of BSP, including biliary clearance, in ketamine or Zoletil anesthetized rats is virtually identical to that in conscious rats and it may be related to blood flow limited hepatic disposition of BSP. Furthermore, they suggest the conscious rat model does not offer methodological advantage and the anesthesia model is suitable for a realistic approximation of the hepatobiliary transport of BSP. Copyright 2009 John Wiley & Sons, Ltd. [source]


Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbits

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2004
Yu C. Kim
Abstract The pharmacokinetics and pharmacodynamics of torasemide were evaluated after intravenous administration of the same total dose of torasemide at a dose of 1mg/kg to rabbits with different infusion times, 1 min (treatment I), 30 min (treatment II) and 2 h (treatment III). The loss of water and electrolytes in urine induced by torasemide was immediately replaced with infusion of an equal volume of lactated Ringer's solution. All the pharmacokinetic parameters of torasemide, such as total area under the plasma concentration,time curve from time zero to time infinity (AUC), total body clearance (CL), apparent volume of distribution at steady state (Vss), terminal half-life and mean residence time (MRT), were independent of infusion times. However, the 8h urine output (235, 534 and 808 ml) and 8h urinary excretion of sodium (24.2, 80.1 and 89.2 mmol) and chloride (27.1, 89.2 and 94.0 mmol) were significantly greater in treatments II and III than those in treatment I, although the total 8 h urinary excretion of unchanged torasemide (1210, 1210 and 1310 g) were not significantly different among the three treatments. This could be due to the higher diuretic efficiencies in treatments II and III. Copyright 2004 John Wiley & Sons, Ltd. [source]


Rapid determination method of caffeine and application to monitoring of caffeine-assisted chemotherapy

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004
Masami Kawahara
Abstract Caffeine-assisted chemotherapy for bone and soft tissue tumours is very effective. However, high serum caffeine concentrations cause severe side effects, so monitoring of the serum level during therapy is important. For this purpose, a rapid determination method was established by high-performance liquid chromatography after solid-phase extraction. This method can measure caffeine and its three major metabolites in serum samples within 8 min. The mean serum caffeine concentrations of patients were 34.67.8, 54.511.9 and 73.012.8 ,g/ml at 24, 48 and 72 h, respectively, after the start of a 1500 mg/m2/day continuous infusion for 72 h. The distribution volume of caffeine was 0.650.23 l/kg, and the total body clearance was 0.0250.011 l/h/kg, which was one-third of the reported low dose clearance. The appropriate infusion rate was calculated to avoid severe side effects in the final phase of the infusion by using a one-compartment constant infusion model based on the serum levels measured at 24 and 48 h. Caffeine clearance did not correlate with the metabolite/caffeine ratio in serum at any time. It is concluded that individual monitoring with this method for the purpose of dose adjustment is useful for avoiding the side effects of caffeine-assisted chemotherapy. Copyright 2004 John Wiley & Sons, Ltd. [source]


Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2004
Micha Levi
Abstract Purpose,Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance. Methods,Rat livers were implanted with Walker-256 tumors. The tumor-bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR-1065 concentrations in the blood, liver and tumor were measured at various times. Results,The WR-1065 tumor portal dosing AUC15,60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one-fifth of that following systemic dosing. The portal dosing WR-1065 liver AUC15,60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR-1065 following portal dosing were up to 8-fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR-1065 was greater following portal vs systemic amifostine. Conclusions,Amifostine may provide increased liver protection and decreased tumor protection from radio- or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR-1065, which is associated with hypotension. Copyright 2004 John Wiley & Sons, Ltd. [source]


Dose-dependent pharmacokinetics of 1-(2-Deoxy- , - D - ribofuranosyl)-2,4-difluoro-5-iodobenzene: A potential mimic of 5-iodo-2,-deoxyuridine

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2003
Panteha Khalili
Abstract The dose-range pharmacokinetics of l-(2-deoxy- , - D -ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C -aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from ,32 ml/min/kg at a dose of 15 mg/kg, to ,19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml,1) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% (,0.19 kg min ml,1) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from ,37 ml/min/kg to ,17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance. For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens. Copyright 2003 John Wiley & Sons, Ltd. [source]


Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2003
Nobuhito Shibata
Abstract Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.780.10 to 0.380.03 ,g h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.300.06 to 0.570.05 ,g h/ml and from 17.631.66 to 4.180.94 ,g h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake. Copyright 2003 John Wiley & Sons, Ltd. [source]


Pharmacokinetics and dose proportionality of BMS-204352 after intraarterial administration to rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002
Rajesh Krishna
Abstract BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in rats. In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels. Serial blood samples were collected for up to 24 h post-dose and plasma samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non-compartmental method. Results revealed a gender difference in the pharmacokinetics of BMS-204352 in rats at all doses excluding the first (i.e., 0.4 mg/kg) dose panel. BMS-204352 peak plasma concentration (Cmax) and area under the plasma concentration,time curve (AUC) values increased in a proportion greater than the increment in dose. Specifically, as dose increased in the ratio 1:5:12.5:25, Cmax increased in the ratio 1:7:18:31 in male rats and 1:7:22:51 in female rats. The respective AUC ratios were 1:6:20:42 in male rats and 1:12:29:77 in female rats. Mean total body clearance (CLT) values for BMS-204352 ranged from 879,3242 ml/h/kg over the four dose levels and generally decreased with increase in dose. Similarly, steady state volume of distribution (VSS) values ranged from 3621,8933 ml/kg over the four dose levels and generally decreased with increase in dose. However, mean residence time (MRT) and elimination half-life (T1/2) values for BMS-204352 were independent of dose and ranged from 2.42,4.54 to 2.08,4.70 h, respectively. In conclusion, BMS-204352 appears to exhibit dose-dependent pharmacokinetics in rats. In addition, there appeared to be some evidence of gender related differences in the pharmacokinetics of BMS-204352. Copyright 2002 John Wiley & Sons, Ltd. [source]


Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2001
Eun J. Kim
Abstract The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to , - and , -globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration,time curve from time zero to time infinity (1012 compared with 2472 ,g min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 ,g, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0,30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats. Copyright 2001 John Wiley & Sons, Ltd. [source]


The pharmacokinetics of ethosuximide enantiomers in the rat

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001
J. Mifsud
Abstract A chiral gas chromatographic assay previously developed for quantitative analysis of ethosuximide and its major metabolites in rat urine has been adapted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious rats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacokinetic parameters were estimated using standard non-compartmental methods. Comparison of the pharmacokinetic parameters of (S)-ethosuximide and (R)-ethosuximide showed that total body clearance of (R)-ethosuximide was significantly larger than that of (S)-ethosuximide and that elimination half-life was significantly shorter following administration of both 40 mg i.v. and i.p. doses, indicating that there is stereoselective elimination of ethosuximide. However, no significant differences were found between apparent volumes of distribution. In addition, no significant differences were found for either enantiomer between the estimates of the pharmacokinetic parameters obtained following administration as the individual enantiomer and as a constituent of the racemic mixture. This indicates that, at the doses studied, the preferential faster elimination of (R)-ethosuximide is not dependent upon the presence of the (S)-enantiomer. Also, for each enantiomer, the lack of any significant difference between estimates of clearance when administered as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other. Copyright 2001 John Wiley & Sons, Ltd. [source]


Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2010
Joo H. Lee
Abstract Objectives In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration,time curve from time zero to time infinity (AUC) of metabolites, AUCmetabolite/AUCparent drug ratios, or the time-averaged nonrenal and total body clearances (CLNR and CL, respectively) of parent drugs as reported in the literature have been compared. Key findings After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CLint) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. Summary Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans. [source]


Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2008
H. Z. DING
Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 17.14 4.14, 25.79 8.10, 16.67 4.04 (pigs) and 6.11 1.50, 5.64 0.74, 8.20 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (Cmax) of 1.77 0.66, 2.29 0.85 (pigs) and 2.51 0.36, 1.00 0.21 ,g/mL (broilers) attained at tmax of 1.29 0.26, 1.41 0.88 (pigs) and 0.86 0.4, 4.34 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 28.9)% and (105.7 37.1)% (pigs) and (77.0 11.8)% and (54.2 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(Vd(area)) of 4.91 1.88 and 3.10 0.67 L/kg and total body clearances(ClB) of 0.20 0.06 and 0.37 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t1/2ka, t1/2,) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL and <0.1 ,g/mL respectively. [source]


Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2001
H. Z. Ding
Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 3.37 0.46, 4.66 1.34, 7.20 1.92 (pigs) and 2.53 0.82, 6.81 2.04, 3.89 1.19 h (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 9.8 and 42.6 8.2% (pigs) and 72.1 8.1 and 59.6 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 0.27 and 3.40 1.26 L/kg and total body clearances (ClB) of 0.51 0.03 and 1.20 0.20 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 h in pigs, or administered orally every 8 h in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL. [source]