title: Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5 (CCR5) with ritonavir in rats and monkeys: role of CYP3A and P-glycoprotein.
abstract: The mechanisms of pharmacokinetic interactions of a novel anti-human immunodeficiency virus (anti-HIV-1) antagonist of chemokine receptor 5 (CCR5) [2-(R)-[N-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)amino]-3-methylbutanoic acid (MRK-1)] with ritonavir were evaluated in rats and monkeys. MRK-1 was a good substrate for the human (MDR1) and mouse (Mdr1a) multidrug resistance protein transporters and was metabolized by CYP3A isozymes in rat, monkey, and human liver microsomes. Both the in vitro MDR1-mediated transport and oxidative metabolism of MRK-1 were inhibited by ritonavir. Although the systemic pharmacokinetics of MRK-1 in rats and monkeys were linear, the oral bioavailability increased with an increase in dose from 2 to 10 mg/kg. The area under the plasma concentration-time curve (AUC) of MRK-1 was increased 4- to 6-fold when a 2 or 10 mg/kg dose was orally coadministered with 10 mg/kg ritonavir. Further pharmacokinetic studies in rats indicated that P-glycoprotein (P-gp) inhibition by ritonavir increased the intestinal absorption of 2 mg/kg MRK-1 maximally by approximately 30 to 40%, and a major component of the interaction likely resulted from its reduced systemic clearance via the inhibition of CYP3A isozymes. Oral coadministration of quinidine (10 and 30 mg/kg) increased both the extent and the first-order rate of absorption of MRK-1 (2 mg/kg) by approximately 40 to 50% and approximately 100 to 300%, respectively, in rats, thus further substantiating the role of P-gp in modulating the intestinal absorption of MRK-1 in this species. At the 10 mg/kg MRK-1 dose, however, the entire increase in its AUC upon coadministration with ritonavir or quinidine could be attributed to a reduced systemic clearance, and no effects on intestinal absorption were apparent. In contrast to rats, the effects of P-gp in determining the intestinal absorption of MRK-1 appeared less significant in rhesus monkeys at either dose.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey, USA. kumar@merck.com
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Gloria Y
authors.initials: GY
authors.lastname: Kwei
authors.forename: Grace K
authors.initials: GK
authors.lastname: Poon
authors.forename: Susan A
authors.initials: SA
authors.lastname: Iliff
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Franklin
authors.forename: Varsha
authors.initials: V
authors.lastname: Didolkar
authors.forename: Regina W
authors.initials: RW
authors.lastname: Wang
authors.forename: Masayo
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Shuet-Hing Lee
authors.initials: SH
authors.lastname: Chiu
authors.forename: Jiunn H
authors.initials: JH
authors.lastname: Lin
authors.forename: Paul G
authors.initials: PG
authors.lastname: Pearson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D065100:CCR5 Receptor Antagonists; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D000882:Haplorhini; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D011485:Protein Binding; D011720:Pyrazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: C473211:2-(N-methyl-N-(((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(3-fluorophenyl)cyclopent-1-yl)amino)-3-methylbutanoic acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065100:CCR5 Receptor Antagonists; D017320:HIV Protease Inhibitors; D011720:Pyrazoles; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D014633:Valine; D011802:Quinidine; D019438:Ritonavir