Clinical Pharmacology & Therapeutics
August 10, 2011
Kazuya Maeda, Yasumasa Ikeda, Tomoe Fujita et al.
207 citations
Atorvastatin, a cholesterol-lowering drug, is cleared from the body by being taken up into the liver via organic anion transporting polypeptides (OATPs) and then broken down by the enzyme CYP3A4. A clinical study using a microdose cocktail given to eight healthy volunteers showed that blocking OATPs with rifampicin increased atorvastatin's exposure 12-fold, while blocking CYP3A4 with itraconazole had no effect. This demonstrates that hepatic uptake via OATPs, not metabolism by CYP3A4, is the dominant process for eliminating atorvastatin at a subtherapeutic dose.
Chemical Research in Toxicology
May 1, 1992
L.y. Lin, Yoshito Kumagai, Arthur K. Cho
67 citations
Rat brain microsomes convert MDA and MDMA into dihydroxyamphetamine (DHA) and dihydroxymethamphetamine (DHMA), respectively. This demethylenation requires NADPH and is strongly inhibited by carbon monoxide/oxygen, indicating involvement of cytochrome P450. The process is inhibited by desipramine, imipramine, and methimazole but not by SKF-525A or alpha-naphthoflavone. Biphasic Lineweaver-Burk plots suggest multiple isozymes may be involved, and no significant stereoselectivity is observed. Catechol formation is 2.6 times greater in phosphate buffer than HEPES buffer, but this difference disappears with desferal and hydroxyl radical scavengers. Sensitivity to catalase and stimulation by ferric ion and EDTA indicate both a cytochrome P450-mediated component and a chemical component involving hydroxyl radicals.
Clinical Pharmacology & Therapeutics
June 29, 2011
Kazuya Maeda, Junichi Takano, Yasumasa Ikeda et al.
50 citations
Microdosing studies help identify early pharmacokinetic properties of drugs in humans, but nonlinearity between microdose and therapeutic dose due to saturation of metabolic enzymes and transporters is a concern. In healthy subjects, verapamil and quinidine, substrates of MDR1 and CYP3A4, showed dose-dependent pharmacokinetics. Dose-normalized AUC values increased 2.6-fold for quinidine and 2.3-fold for verapamil at therapeutic doses compared to microdoses, suggesting saturation of MDR1 and/or CYP3A4 in the small intestine causes nonlinearity.