Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients

Nora Lee, Kazuya Maeda, Shinya Fukizawa, Ichiro Ieiri, Atsuko Tomaru, Hironobu Akao, Kenji Takeda, Mizuho Iwadare, Osamu Niwa, Tougen Masauji, Naoe Yamane, Kouji Kajinami, Hiroyuki Kusuhara, Yuichi Sugiyama

Research output: Contribution to journalArticle

Abstract

The present study investigated whether the clinical pharmacokinetics of atorvastatin can be predicted from the results of microdosing study in Japanese patients with hypercholesterolemia whose SLCO1B1 and ABCG2 polymorphisms were analyzed. Forty seven statin-naive patients clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. Microdose (100 μg) of atorvastatin was orally administered followed by therapeutic dose (10 mg) administration. Transport studies were performed with BCRP-expressing membrane vesicles. The dose-normalized plasma AUC following the therapeutic dose of atorvastatin was positively correlated with that following its microdose, but the AUC increased more than dose proportionally from microdose to therapeutic dose. The patients carrying SLCO1B1 c.521TC showed a significantly higher AUC compared with those carrying c.521TT following the microdose (175%) and therapeutic dose (139%). On the other hand, SLCO1B1 c.388G or ABCG2 c.421A variant alleles did not significantly affect the pharmacokinetics of atorvastatin. Atorvastatin showed ATP-dependent transport in BCRP-expressing membrane vesicles and it inhibited rosuvastatin transport with Ki of 6.3 ± 2.9 μM (mean ± SD). Microdosing study appears to be feasible to roughly estimate the pharmacokinetic and pharmacogenetic profiles of atorvastatin following the oral therapeutic dose in hypercholesterolemic patients.

Original languageEnglish
Pages (from-to)387-395
Number of pages9
JournalDrug metabolism and pharmacokinetics
Volume34
Issue number6
DOIs
Publication statusPublished - Dec 2019

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Pharmacogenetics
Pharmacokinetics
Area Under Curve
Therapeutics
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Membranes
Atorvastatin Calcium
Clinical Studies
Hypercholesterolemia
LDL Cholesterol
Cross-Over Studies
Adenosine Triphosphate
Alleles

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients. / Lee, Nora; Maeda, Kazuya; Fukizawa, Shinya; Ieiri, Ichiro; Tomaru, Atsuko; Akao, Hironobu; Takeda, Kenji; Iwadare, Mizuho; Niwa, Osamu; Masauji, Tougen; Yamane, Naoe; Kajinami, Kouji; Kusuhara, Hiroyuki; Sugiyama, Yuichi.

In: Drug metabolism and pharmacokinetics, Vol. 34, No. 6, 12.2019, p. 387-395.

Research output: Contribution to journalArticle

Lee, N, Maeda, K, Fukizawa, S, Ieiri, I, Tomaru, A, Akao, H, Takeda, K, Iwadare, M, Niwa, O, Masauji, T, Yamane, N, Kajinami, K, Kusuhara, H & Sugiyama, Y 2019, 'Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients', Drug metabolism and pharmacokinetics, vol. 34, no. 6, pp. 387-395. https://doi.org/10.1016/j.dmpk.2019.08.004
Lee, Nora ; Maeda, Kazuya ; Fukizawa, Shinya ; Ieiri, Ichiro ; Tomaru, Atsuko ; Akao, Hironobu ; Takeda, Kenji ; Iwadare, Mizuho ; Niwa, Osamu ; Masauji, Tougen ; Yamane, Naoe ; Kajinami, Kouji ; Kusuhara, Hiroyuki ; Sugiyama, Yuichi. / Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients. In: Drug metabolism and pharmacokinetics. 2019 ; Vol. 34, No. 6. pp. 387-395.
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AU - Maeda, Kazuya

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AU - Ieiri, Ichiro

AU - Tomaru, Atsuko

AU - Akao, Hironobu

AU - Takeda, Kenji

AU - Iwadare, Mizuho

AU - Niwa, Osamu

AU - Masauji, Tougen

AU - Yamane, Naoe

AU - Kajinami, Kouji

AU - Kusuhara, Hiroyuki

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