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Absolute Oral Bioavailability (absolute + oral_bioavailability)
Selected AbstractsFormulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agentJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2002Bruce J. Aungst Abstract DPC 961 is a low-solubility, high-permeability, second-generation non-nucleoside reverse transcriptase inhibitor. The purpose of these studies was to evaluate the effects of drug substance and formulation variables on DPC 961 oral absorption, and to compare fed and fasted state oral absorption. To accomplish this, groups of four to six dogs were dosed with various formulations of DPC 961 under fasted or fed conditions, and DPC 961 pharmacokinetics were examined. Absolute oral bioavailability, based on i.v. AUC in the same dogs, was 24% after a suspension dose in fasted dogs and was 51% in fed dogs. Bioavailability with an unoptimized tablet formulation was 30% in fasted dogs and 86% in fed dogs. DPC 961 oral absorption was shown to be dependent on drug substance particle size in fasted dogs, after dosing with a tablet formulation where only the drug substance particle size was varied, but there was no difference in fed dogs. AUC and Cmax increased in proportion with increases in tablet strength from 100 to 400 mg, using tablets manufactured from a common granulation. Tablets made with 50 and 66% drug loadings showed similar relative oral bioavailabilities. Tablets prepared with two different polymorphic forms of DPC 961 were also compared, and these were found to be equivalent. These studies provided a useful component of the formulation development process, to help identify and control the variables affecting oral absorption of this potential new therapeutic agent. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1390,1395, 2002 [source] Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2007E. LALLEMAND Moxidectin is a long-acting anthelmintic drug for which little is known about its kinetic behaviour in dogs and its oral absolute bioavailability has never been reported. We studied the pharmacokinetics of moxidectin in dogs, with a special emphasis on oral bioavailability and the influence of lipid co-administration, by using a semi-simultaneous method of administration. Ten Beagle dogs were dosed orally and then intravenously (i.v.) with 0.2 mg/kg moxidectin. The oral application was conducted with or without corn oil co-administration. Moxidectin concentration,time profiles in plasma were analysed using a compartmental modelling approach, designed to fit the oral and i.v. kinetic disposition curves simultaneously. In contrast to what happens in other species, our study indicates that the bioavailability of orally given moxidectin in dogs is nearly total (90.2 ± 7.4%), and is not enhanced by lipid co-administration. The clearance, the volume of distribution, the mean residence time and the terminal half-life were similar to what was already described for other species. Finally our trial suggests that the body condition (degree of obesity) is likely to be a major determinant of moxidectin kinetics in dogs because of its modulation of the volume of distribution that indirectly controls the terminal half-life of the drug. [source] Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007Young Hoon Kim Abstract The dose-dependency of the pharmacokinetics of a new Na+/H+ exchanger inhibitor, KR-33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR-33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (Vss), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09,0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR-33028 was rapidly absorbed, and this was consistent with high Caco-2 Papp values found in vitro. There were nonlinear increases in AUC and Cmax, and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5,0.7%) and oral (0.2,0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first-pass metabolism. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2006Beom Soo Shin Abstract This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8,1.1 h, 59.6,68.0 ml/min/kg and 2.4,2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%,0.020% and 0.049%±0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9,1.1 h, 520.3,621.2 ml/min/kg and 67.6,84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats. Copyright © 2005 John Wiley & Sons, Ltd. [source] Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effectBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001Eun J. Kim Abstract The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration,time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 ,g min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC0,12 h at 50 mg/kg (25.1, 18.3 and 49.2 ,g min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 ,g min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats. Copyright © 2001 John Wiley & Sons, Ltd. [source] | ||||||||||