title: Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-glycoprotein), and pravastatin (OATP1B1) as probe drugs.
abstract: We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC0-24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)0-24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.
authors: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors: Ichiro
authors: I
authors: Ieiri
authors: Shyohei
authors: S
authors: Tsunemitsu
authors: Kazuya
authors: K
authors: Maeda
authors: Yukie
authors: Y
authors: Ando
authors: Noritomo
authors: N
authors: Izumi
authors: Miyuki
authors: M
authors: Kimura
authors: Naoe
authors: N
authors: Yamane
authors: Tsuyoshi
authors: T
authors: Okuzono
authors: Mariko
authors: M
authors: Morishita
authors: Naoki
authors: N
authors: Kotani
authors: Eri
authors: E
authors: Kanda
authors: Mariko
authors: M
authors: Deguchi
authors: Kyoko
authors: K
authors: Matsuguma
authors: Shunji
authors: S
authors: Matsuki
authors: Takeshi
authors: T
authors: Hirota
authors: Shin
authors: S
authors: Irie
authors: Hiroyuki
authors: H
authors: Kusuhara
authors: Yuichi
authors: Y
authors: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism; D017035:Pravastatin / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D019258:Saquinavir / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D016593:Terfenadine; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017035:Pravastatin; D019258:Saquinavir; D019438:Ritonavir; D008874:Midazolam