High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4 *16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database.

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High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4 *16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database.

High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4 *16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database.

アブストラクト	Drug interactions between atorvastatin and cytochrome P450 (P450) 3A substrates/inhibitors lead to an increased incidence of skeletal muscle or hepatic toxicity. However, in this survey, among 483 Japanese subjects administered atorvastatin alone, more than half (258) experienced statin intolerance and were unable to continue using the drug. Although many factors underly atorvastatin toxicity, the intrinsic clearance rate might be a contributing causal factor. The impaired P450 3A4 p.Thr185Ser variant, CYP3A4 16 (rs12721627), has been identified in East Asians with an allele frequency of 2.2%. Pharmacokinetically modeled plasma concentrations of atorvastatin increased after a virtual oral dose of 40 mg in CYP3A4 16 homozygotes; the maximum concentration and area under the concentration curve, respectively, were 3.3-fold and 4.2-fold those in subjects homozygous for CYP3A4 1. In subjects with CYP3A4 16/ 16, the virtual hepatic concentrations of atorvastatin after daily doses of 10 mg for a week were similar to or higher than the plasma concentrations. These results suggest that the estimated high virtual plasma and hepatic exposures obtained by pharmacokinetic modeling in subjects harboring impaired allele CYP3A4 16 may be one of the causal factors for statin intolerance in a manner similar to the well-known drug interactions caused by co-administrations of CYP3A inhibitors.
ジャーナル名	Drug metabolism and pharmacokinetics
Pubmed追加日	2023/2/7
投稿者	Adachi, Koichiro; Ohyama, Katsuhiro; Tanaka, Yoichi; Sato, Tasuku; Murayama, Norie; Shimizu, Makiko; Saito, Yoshiro; Yamazaki, Hiroshi
組織名	Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.;School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji,;Tokyo, 192-0392, Japan.;National Institute of Health Sciences, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501,;Japan.;Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. Electronic;address: hyamazak@ac.shoyaku.ac.jp.
Pubmed リンク	https://www.ncbi.nlm.nih.gov/pubmed/36746706/