title: Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid-induced osteonecrosis in a rabbit model.
abstract: Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid-induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n = 15), inhibitor (itraconazole, group I; n = 15), or saline (group C, n = 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p < 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 +/- 5.9%) was significantly lower than in group I (69.8 +/- 20.8%) and group C (51.5 +/- 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid-induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers.
authors.affiliation: Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Iwakiri
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oda
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kaneshiro
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Iwaki
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ohashi
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
mesh_terms: D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005271:Femur Head Necrosis / Q000139:chemically induced / Q000453:epidemiology* / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D015994:Incidence; D017964:Itraconazole / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008775:Methylprednisolone / Q000494:pharmacology*; D008874:Midazolam / Q000493:pharmacokinetics; D010634:Phenobarbital / Q000494:pharmacology; D015995:Prevalence; D011817:Rabbits; D012307:Risk Factors