Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs

Ichiro Ieiri, Shyohei Tsunemitsu, Kazuya Maeda, Yukie Ando, Noritomo Izumi, Miyuki Kimura, Naoe Yamane, Tsuyoshi Okuzono, Mariko Morishita, Naoki Kotani, Eri Kanda, Mariko Deguchi, Kyoko Matsuguma, Shunji Matsuki, Takeshi Hirota, Shin Irie, Hiroyuki Kusuhara, Yuichi Sugiyama

研究成果: ジャーナルへの寄稿記事

23 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)654-661
ページ数8
ジャーナルJournal of Clinical Pharmacology
53
発行部数6
DOI
出版物ステータス出版済み - 6 1 2013

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fexofenadine
Saquinavir
Cytochrome P-450 CYP3A
Pravastatin
Ritonavir
Midazolam
Glycoproteins
Pharmacokinetics
Pharmaceutical Preparations
Drug Interactions
Area Under Curve
Healthy Volunteers
Safety
Liver

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

これを引用

Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs. / Ieiri, Ichiro; Tsunemitsu, Shyohei; Maeda, Kazuya; Ando, Yukie; Izumi, Noritomo; Kimura, Miyuki; Yamane, Naoe; Okuzono, Tsuyoshi; Morishita, Mariko; Kotani, Naoki; Kanda, Eri; Deguchi, Mariko; Matsuguma, Kyoko; Matsuki, Shunji; Hirota, Takeshi; Irie, Shin; Kusuhara, Hiroyuki; Sugiyama, Yuichi.

:: Journal of Clinical Pharmacology, 巻 53, 番号 6, 01.06.2013, p. 654-661.

研究成果: ジャーナルへの寄稿記事

Ieiri, I, Tsunemitsu, S, Maeda, K, Ando, Y, Izumi, N, Kimura, M, Yamane, N, Okuzono, T, Morishita, M, Kotani, N, Kanda, E, Deguchi, M, Matsuguma, K, Matsuki, S, Hirota, T, Irie, S, Kusuhara, H & Sugiyama, Y 2013, 'Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs', Journal of Clinical Pharmacology, 巻. 53, 番号 6, pp. 654-661. https://doi.org/10.1002/jcph.62
Ieiri, Ichiro ; Tsunemitsu, Shyohei ; Maeda, Kazuya ; Ando, Yukie ; Izumi, Noritomo ; Kimura, Miyuki ; Yamane, Naoe ; Okuzono, Tsuyoshi ; Morishita, Mariko ; Kotani, Naoki ; Kanda, Eri ; Deguchi, Mariko ; Matsuguma, Kyoko ; Matsuki, Shunji ; Hirota, Takeshi ; Irie, Shin ; Kusuhara, Hiroyuki ; Sugiyama, Yuichi. / Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs. :: Journal of Clinical Pharmacology. 2013 ; 巻 53, 番号 6. pp. 654-661.
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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.",
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T1 - Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs

AU - Ieiri, Ichiro

AU - Tsunemitsu, Shyohei

AU - Maeda, Kazuya

AU - Ando, Yukie

AU - Izumi, Noritomo

AU - Kimura, Miyuki

AU - Yamane, Naoe

AU - Okuzono, Tsuyoshi

AU - Morishita, Mariko

AU - Kotani, Naoki

AU - Kanda, Eri

AU - Deguchi, Mariko

AU - Matsuguma, Kyoko

AU - Matsuki, Shunji

AU - Hirota, Takeshi

AU - Irie, Shin

AU - Kusuhara, Hiroyuki

AU - Sugiyama, Yuichi

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

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JF - Journal of Clinical Pharmacology

SN - 0091-2700

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