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Cmax Values (cmax + value)
Selected AbstractsEffect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Xiaoxia Zheng Abstract A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4,-chloro- N -methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the Cmax value (1.2 µM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC50 value (3.2 µM). On the other hand, ZXX2-79 (4b) (SO2NH derivative of ZXX2-77 (4a); 4-amino-4,-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC50,=,12 µM, COX-2 IC50,=,150 µM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (Cmax,=,16 µM at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N -methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] Interaction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahuricaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KAZUHISA ISHIHARA The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2,- and 16,-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg,1 dose. 6,-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg,1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg,1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg,1), but not low dose (0.3 g kg,1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg,1. It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs. [source] Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2002Khalid Matalka We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC0,,) were 480 ± 216 and 832 ± 325 ngh/mL, maximum plasma concentrations (Cmax) were 310 ± 187 and 481 ± 185 ng/mL, and times required to reach the maximum concentration (tmax) were 1.13 ± 0.22 and 1.09 ± 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC0,, were 256 ± 122 and 383 ± 158 ngh/mL, Cmax values were 57 ± 29 and 72.9 ± 33.6 ng/mL and tmax values were 4.28 ± 1.45 and 4.05 ± 01.22 h for 10 and 20 mg doses, respectively. The Cmax values of enalapril were ,10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r=,0.95 with P < 0.001 and r=,0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids. [source] Scintigraphic study to investigate the effect of food on a HPMC modified release formulation of UK-294,315JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2009J. Davis Abstract The objective of the study was to use the combined approach of gamma scintigraphy and pharmacokinetics, in order to understand the mechanisms explaining the pharmacokinetic differences observed for a modified release (MR) formulation, when administered either in the fed or fasted state. Ten healthy subjects were recruited into a randomized three period single dose study, each subject receiving UK-294,315 40 mg IR (fasted), 100 mg MR (fasted) or 100 mg MR (after a high fat meal). Cmax values were markedly higher for the MR tablet in the fed state versus fasted and mean residence time was about 3 h longer for fasted versus fed; there was little difference in apparent oral clearance. In the fasted state, average gastric emptying of the intact tablet occurred at 1.2 h postdose, with gastric emptying of intact tablet observed in all subjects. In the fed state, rapid disintegration of the MR tablet was observed by scintigraphy, with 7/9 subjects showing complete disintegration in the stomach. Complete disintegration occurred 10.1 h postdose in the fasted state versus 5.9 h after a high fat meal. The study showed that in the fed state, the MR tablet eroded more rapidly than in the fasted state, leading to an overall increase in the rate of absorption. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1568,1576, 2009 [source] ,-cyclodextrin reduces bioavailability of orally administered [3H]benzo[a]pyrene in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2005Goran Westerberg Abstract The excretion and plasma kinetics of total radioactivity were studied following single oral administration of [3H]benzo[a]pyrene after multiple oral administration of ,-cyclodextrin at 0, 5, 50, or 500 mg/kg/day. The AUC and Cmax values in male and female rats following administration of [3H]benzo[a]pyrene in combination with 5 to 500 mg/kg ,-cyclodextrin were considerably lower than that in rats administered [3H]benzo[a]pyrene alone. At all dose levels of ,-cyclodextrin, the excretion of total radioactivity was almost entirely via feces, with <2% recovered in urine, demonstrating either that absorption of the orally administered dose was low or that, for any absorbed material, biliary excretion was the main route of excretion. However, following administration of vehicle, up to 5% of the administered radioactivity was recovered in the urine, suggesting that absorption may have been reduced by the presence of ,-cyclodextrin in the intestine. At all dose levels of ,-cyclodextrin, there was minimal retention of radioactivity in the carcase at the end of the collection period. ,-Cyclodextrin did not affect the apparent terminal half-life of radioactivity. Therefore, the reduced systemic exposure of rats to radioactivity in the presence of ,-cyclodextrin is likely related to a reduced oral bioavailability. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:114,119, 2005 [source] Placental transfer and pharmacokinetics of allopurinol in late pregnant sows and their fetusesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008A. J. VAN DIJK Xanthine oxidoreductase (XOR) is a key enzyme in the evolvement of reperfusion injury resulting from birth asphyxia, a common cause of decreased viability and perinatal mortality in newborn piglets under farm conditions. At present no standard pharmacological intervention strategy is available to reduce these adverse effects of birth asphyxia. In the present study we aimed to evaluate placental transfer of allopurinol, an inhibitor of XOR. For this purpose, fetal catheterization of the jugular vein was conducted in five late pregnant sows (one fetus per sow). At 24,48 h after surgery, sows received allopurinol (15 mg/kg body weight; i.v.) and pharmacokinetics of allopurinol and its active metabolite oxypurinol were measured in both late pregnant sows and fetuses. Maternal and fetal blood samples were collected during and after allopurinol administration. Maternal Cmax values averaged 41.90 ,g/mL (allopurinol) and 3.68 ,g/mL (oxypurinol). Allopurinol crossed the placental barrier as shown by the average fetal Cmax values of 5.05 ,g/mL at 1.47 h after allopurinol administration to the sow. In only one fetus low plasma oxypurinol concentrations were found. Incubations of subcellular hepatic fractions of sows and 24-h-old piglets confirmed that allopurinol could be metabolized into oxypurinol. In conclusion, we demonstrated that allopurinol can cross the placental barrier, a prerequisite for further studies evaluating the use of allopurinol as a neuroprotective agent to reduce the adverse effects following birth asphyxia in neonatal piglets. [source] Population pharmacokinetics of pyrazinamide in elephantsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005M. ZHU This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20,30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0,24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with Tmax at or before 2 h regardless of the method of drug administration. Cmax at a mean dose of 25.6 (±4.6) mg/kg was 19.6 (±9.5 ,g/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 ± 4.2 mg/kg, Cmax was 25% (4.87 ± 4.89 ,g/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 ± 15.2 mg/kg yielded Cmax of 12.3 ± 6.3 ,g/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher Cmax and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved Cmax values are below the recommended 20,50 ,g/mL range. [source] Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats,JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005S. A. ROBERTSON Data allowing rational use of analgesics in cats are limited. Pharmacokinetics and pharmacodynamics of fentanyl were studied in cats. Plasma fentanyl concentrations were measured using radioimmunoassay in a crossover study in six cats after 10 ,g/kg (i.v.) or by application of fentanyl in pluronic lecithin organogel (PLO) to the inner ear pinna. On a separate occasion thermal thresholds were measured after i.v. fentanyl (10 ,g/kg) or saline. Plasma fentanyl concentrations reached 4.7,8.31 ng/mL 2 min after i.v. administration and were undetectable after 95 min. Fentanyl was not detected in plasma at any time after PLO use. Thermal thresholds did not change following saline administration but were increased above baseline from 5 to 110 min after i.v. fentanyl. In this model a plasma concentration of >1.07 ng/mL was required to provide analgesia. Plasma concentrations were measured in additional cats after intranasal or oral dosing (2 ,g/kg) and after 30 ,g/kg in PLO gel. After oral and nasal dosing, Cmax values were 0.96 and 1.48 ng/mL at 5 and 2 min, respectively. Plasma fentanyl was not detected after application of the higher dose of fentanyl in PLO. [source] Evaluation of the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastasesASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 1 2010Mark A ROSENTHAL Abstract Aim: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. Methods: A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. Results: Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC0,12 h was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean Cmax values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of ,43.4 percent (200-mg group) and ,34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). Conclusion: MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study. [source] Effect of concomitant colestipol hydrochloride administration on the bioavailability of diltiazem from immediate- and sustained-release formulationsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2002Scott W. Turner Abstract Effects of concomitant colestipol administration on plasma concentrations of diltiazem and desacetyldiltiazem from immediate-release (IR) and sustained-release (SR) formulations were assessed in two studies. In the first study, 12 subjects received 120-mg diltiazem hydrochloride (diltiazem) SR capsules or 120-mg diltiazem IR tablets administered alone and in combination with colestipol hydrochloride (colestipol). Following concomitant administration of SR diltiazem with colestipol, AUC0,, and Cmax, respectively, were 22 and 36% less, and were 27 and 33% lower for IR diltiazem. In the second study, subjects received 120-mg diltiazem SR capsules at staggered times, without colestipol, 1 h prior to or 4 h following multiple doses of colestipol. A 17% decrease in AUC0,, was observed when diltiazem was taken 1 h before colestipol was given, and a 22% decrease when diltiazem was taken 4 h after colestipol, relative to diltiazem SR alone. Cmax values were similarly decreased. Results from these two studies show that colestipol can cause a significant decrease in diltiazem absorption from both IR and SR dosage forms. Staggering the administration of colestipol and diltiazem SR did not blunt this effect, indicating that concomitant administration of diltiazem and colestipol should be used with caution, and that the efficacy of diltiazem should be monitored to assure adequate dosing. Copyright © 2002 John Wiley & Sons, Ltd. [source] Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Andries Pelser Abstract The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, Cmax, tmax) following intranasal, oral and intravenous administrations. Subjects (six male Sprague,Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25±1°C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid,liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (Cmax) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve Cmax for the intranasal route (tmax=0.5 h) was faster than for the oral route (tmax=1.5 h), but no statistically significant differences between the Cmax values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa. Copyright © 2002 John Wiley & Sons, Ltd. [source] The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2000J. J. Miceli Aims, To evaluate the effect of steady-state carbamazepine administration on the steady-state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel-group study. Methods, Twenty-five subjects were randomized to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine replaced by placebo. Pharmacokinetic data were obtained on days 3 and 28. Results, Nine subjects in group 1 and 10 in group 2 completed all three treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. The mean half-life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study. Conclusions, Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady-state exposure to ziprasidone that is believed to be clinically insignificant. [source] | ||||||||||