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Low hepatic cytochrome P450 3A activity is a risk for corticosteroid‐induced osteonecrosis
Author(s) -
Kaneshiro Yasunori,
Oda Yutaka,
Iwakiri Kentaro,
Masada Toshiaki,
Iwaki Hiroyoshi,
Hirota Yoshio,
Kondo Kyoko,
Takaoka Kunio
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.07.004
Subject(s) - medicine , odds ratio , cyp3a , midazolam , pathogenesis , corticosteroid , gastroenterology , confidence interval , case control study , urology , pharmacology , cytochrome p450 , metabolism , sedation
Background Osteonecrosis of the femoral head (ONFH) is one of the major side effects of corticosteroid therapy. Because corticosteroids are metabolized by hepatic cytochrome P450 (CYP) 3A, a low endogenous activity of this enzyme may contribute to the pathogenesis of ONFH. The purpose of this study was to examine the possible association of hepatic CYP3A activity and the susceptibility to ONFH in patients treated with corticosteroids. Methods In this prospective controlled study we measured the clearance of intravenous midazolam (0.25 mg/kg) to estimate hepatic CYP3A activity in patients with steroid‐induced ONFH (n = 26), patients with alcohol‐related ONFH (n = 29), and non‐ONFH control patients (n = 75) undergoing orthopedic surgery. Midazolam clearance was compared between the groups, and the relationship between the level of hepatic CYP3A activity and the prevalence of ONFH was evaluated by multivariate analysis. Results Midazolam clearance in patients with steroid‐induced ONFH was significantly lower than that in control patients and patients with alcohol‐related ONFH (7.7 ± 1.8 mL · kg −1 · min −1 versus 11.4 ± 3.5 mL · kg −1 · min −1 and 10.5 ± 2.8 mL · kg −1 · min −1 , respectively; P < .001). Patients with low midazolam clearance (<9.5 mL · kg −1 · min −1 ) had a 9‐fold greater risk for steroid‐induced ONFH (adjusted odds ratio, 9.08 [95% confidence interval, 2.79–29.6]; P < .001). Midazolam clearance did not show a significant correlation with the prevalence of alcohol‐related ONFH. Conclusions Low hepatic CYP3A activity may significantly contribute to the risk for steroid‐induced ONFH. Clinical Pharmacology & Therapeutics (2006) 80 , 396–402; doi: 10.1016/j.clpt.2006.07.004