title: The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation.
abstract: Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5(*)1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5-HLM than in CYP3A5+ HLM with midazolam (K(i) of 15 and 25 microM, respectively) but not with erythromycin (IC(50) of 70 and 54 microM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (K(i) of 7.7 and 54 microM, respectively) and erythromycin (IC(50) of 100 and 350 microM, respectively). As predicted from HLM, with i.v. midazolam, the average (+/- S.D.) in vivo K(i) (K(i,iv)) was significantly higher in CYP3A5(*)1 carriers (24 +/- 17 and 17 +/- 8 microM for homozygous and heterozygous groups, respectively) than in noncarriers (13 +/- 6 microM) (p = 0.02). With the erythromycin breath test, the average K(i,iv) was not different between homozygous CYP3A5(*)1 carriers (30 +/- 12 microM) and noncarriers (58 +/- 53 microM). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.forename: Shana R
authors.initials: SR
authors.lastname: Ludington
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Givens
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
authors.forename: Susan N
authors.initials: SN
authors.lastname: Pusek
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: David K
authors.initials: DK
authors.lastname: Blough
authors.forename: Kazunori
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Roy L
authors.initials: RL
authors.lastname: Hawke
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004917:Erythromycin / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D007313:Insecta / Q000235:genetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004917:Erythromycin; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam