TY - JOUR T1 - Effect of Oral Ketoconazole on Oral and Intravenous Pharmacokinetics of Simvastatin and Its Acid in Cynomolgus Monkeys JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 122 LP - 128 DO - 10.1124/dmd.108.022574 VL - 37 IS - 1 AU - Akihito Ogasawara AU - Masahiro Utoh AU - Kazuo Nii AU - Ayumi Ueda AU - Takahiro Yoshikawa AU - Toshiyuki Kume AU - Koichiro Fukuzaki Y1 - 2009/01/01 UR - http://dmd.aspetjournals.org/content/37/1/122.abstract N2 - Drugs with potential drug-drug interactions (DDIs) may have a limited scope of use and, at worst, may have to be withdrawn from the market. Therefore, during the drug discovery process it is important to select drug candidates with reduced potential for DDIs. In the present study, we evaluated the pharmacokinetics of simvastatin (SV), a typical substrate for cytochrome P450 (P450) 3A, and examined the DDI between SV and ketoconazole (KTZ), a P450 3A inhibitor, in monkeys. SV metabolism in monkey liver and intestinal microsomes was almost completely inhibited by addition of anti-P450 3A4 antiserum. A similar effect was seen in human microsomes, and the IC50 values of KTZ for inhibition of SV metabolism were similar in monkey and human samples. In vivo, there were no significant differences in the pharmacokinetic parameters of SV and SVA after i.v. administration of SV in the presence of KTZ compared with those in controls, probably because of the limited systemic exposure to KTZ. In contrast, the pharmacokinetics of SV and SVA after p.o. administration of SV were significantly influenced by the presence of KTZ, and Cmax and area under the plasma concentration-time curve were approximately 5 to 10 times higher than those after p.o. dosing with SV alone. The increases in systemic SV exposure caused by a concomitant p.o. dose of KTZ in monkeys were similar to those observed in clinical studies, which suggests that monkeys might be a suitable animal model in which to predict DDIs involving P450 3A inhibition. The American Society for Pharmacology and Experimental Therapeutics ER -