title: Time-dependent interaction of ritonavir in chronic use: the power balance between inhibition and induction of P-glycoprotein and cytochrome P450 3A.
abstract: Ritonavir (RTV) is not only an inhibitor but also an immunoreactive inducer of both P-glycoprotein (Pgp) and cytochrome P450 (CYP) 3A in terms of its chronic use. The aim of present study was to test the hypothesis that the power balance between inhibition effects of RTV and induced activities of Pgp and CYP3A depends on the time after last RTV treatment (TimeR) in the chronic use of RTV; rhodamine 123 (Rho) and midazolam (MDZ) were administered at predetermined TimeR to rats pretreated with RTV for 7 days. After oral administration of Rho and MDZ to rats pretreated with RTV for 7 days, the areas under the plasma concentration-time curve of Rho and MDZ were significantly altered depending on TimeR: 1.27-, 0.79-, 0.95-, and 0.11-fold increases over that of the control for Rho at TimeR = 0, 3, 9, and 24 h and 3.12-, 1.50-, 1.27-, and 0.17-fold increases over that of the control for MDZ at TimeR = 0, 3, 9, and 24 h, respectively. These results revealed the presence of the time-dependent interaction of RTV with concomitant drugs in chronic use and should be taken into account in therapeutic strategies for HIV infection.
authors.affiliation: Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, 650-8586, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Mizuhara
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Aoyama
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
authors.affiliation: Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, 650-8586, Japan. Electronic address: nsugioka@pharm.kobegakuin.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D020112:Rhodamine 123; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam