Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model

Dabigatran etexilate (DABE) is a clinical probe substrate for studying drug-drug interaction (DDI) through an intestinal P-glycoprotein (P-gp). A recent in vitro study, however, has suggested a potentially significant involvement of CYP3A-mediated oxidative metabolism of DABE and its intermediate monoester BIBR0951 in DDI following microdose administration of DABE. In this study, the relative significance of CYP3A- and P-gp-mediated pathways to the overall disposition of DABE has been explored using mechanistic physiologically based pharmacokinetic (PBPK) modeling approach. The developed PBPK model linked DABE with its 2 intermediate (BIBR0951 and BIBR1087) and active (dabigatran, DAB) metabolites, and with all relevant drug-specific properties known to date included. The model was successfully qualified against several datasets of DABE single/multiple dose pharmacokinetics and DDIs with CYP3A/P-gp inhibitors. Simulations using the qualified model supported that the intestinal CYP3A-mediated oxidation of BIBR0951, and not the gut P-gp-mediated efflux of DABE, was a key contributing factor to an observed difference in the DDI magnitude following the micro-versus therapeutic doses of DABE with clarithromycin. Both the saturable CYP3A-mediated metabolism of BIBR0951 and the solubility-limited DABE absorption contributed to the relatively modest nonlinearity in DAB exposure observed with increasing doses of DABE. Furthermore, the results suggested a limited role of the gut P-gp, but an appreciable, albeit small, contribution of gut CYP3A in mediating the DDIs following the therapeutic dose of DABE with dual CYP3A/P-gp inhibitors. Thus, a possibility exists for a varying extent of CYP3A involvement when using DABE as a clinical probe in the DDI assessment, across DABE dose levels

DISPOSITION OF L-738,167, A POTENT AND LONG-ACTING FIBRINOGEN RECEPTOR ANTAGONIST, IN DOGS Dose-Dependent Pharmacokinetics

ABSTRACT: L-738,167 is a potent and long-acting fibrinogen receptor antagonist and may be useful for treatment of chronic thrombotic occlusive disorders. The purposes of this study were to characterize the metabolism and disposition of L-738,167, and to investigate factors affecting its pharmacokinetic behaviors in dogs, one of the animal models used in pharmacological and toxicological studies. In vitro and in vivo experiments indicated that L-738,167 was not metabolized to any appreciable extent in dogs. Biliary excretion was found to be the major route (ϳ75%) of drug elimination

ABSORPTION AND DISPOSITION OF IOTHALAMATE.

ABSORPTION AND DISPOSITION OF IOTHALAMATE

In vitro and in vivo CYP3A64 induction and inhibition studies in rhesus monkeys: a preclinical approach for CYP3A-mediated drug interaction studies. Drug Metab Dispos 34:1546–1555.

ABBREVIATIONS: MDZ, midazolam; 1'-OH MDZ, 1'-hydroxy midazolam; 4-OH MDZ, 4-hydroxy midazolam; AUC, area under plasma concentration-time curve; C max , peak plasma concentration; CL, plasma clearance; F h , hepatic availability; V dss , volume of distribution at steady-state; t 1/2 , half-life; i.pv., intra-hepatic portal vein; IS, internal standard; LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry

Cyclosporine metabolism by rat liver microsomes. Drug Metab. Dispos

ABSTRACT: Cyclosponn