RT Journal Article
SR Electronic
T1 Pharmacokinetics and Interactions of a Novel Antagonist of Chemokine Receptor 5 (CCR5) with Ritonavir in Rats and Monkeys: Role of CYP3A and P-Glycoprotein
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1161
OP 1171
DO 10.1124/jpet.102.045096
VO 304
IS 3
A1 Sanjeev Kumar
A1 Gloria Y. Kwei
A1 Grace K. Poon
A1 Susan A. Iliff
A1 Yanfeng Wang
A1 Qing Chen
A1 Ronald B. Franklin
A1 Varsha Didolkar
A1 Regina W. Wang
A1 Masayo Yamazaki
A1 Shuet-Hing Lee Chiu
A1 Jiunn H. Lin
A1 Paul G. Pearson
A1 Thomas A. Baillie
YR 2003
UL http://jpet.aspetjournals.org/content/304/3/1161.abstract
AB 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 ∼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 ∼40 to 50% and ∼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. The American Society for Pharmacology and Experimental Therapeutics