RT Journal Article
SR Electronic
T1 The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 146
OP 154
DO 10.1124/dmd.107.018382
VO 36
IS 1
A1 Nina Isoherranen
A1 Shana R. Ludington
A1 Raymond C. Givens
A1 Jatinder K. Lamba
A1 Susan N. Pusek
A1 E. Claire Dees
A1 David K. Blough
A1 Kazunori Iwanaga
A1 Roy L. Hawke
A1 Erin G. Schuetz
A1 Paul B. Watkins
A1 Kenneth E. Thummel
A1 Mary F. Paine
YR 2008
UL http://dmd.aspetjournals.org/content/36/1/146.abstract
AB 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 (Ki of 15 and 25 μM, respectively) but not with erythromycin (IC50 of 70 and 54 μM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (Ki of 7.7 and 54 μM, respectively) and erythromycin (IC50 of 100 and 350 μM, respectively). As predicted from HLM, with i.v. midazolam, the average (± S.D.) in vivo Ki (Ki,iv) was significantly higher in CYP3A5*1 carriers (24 ± 17 and 17 ± 8 μM for homozygous and heterozygous groups, respectively) than in noncarriers (13 ± 6 μM) (p = 0.02). With the erythromycin breath test, the average Ki,iv was not different between homozygous CYP3A5*1 carriers (30 ± 12 μM) and noncarriers (58 ± 53 μM). 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. The American Society for Pharmacology and Experimental Therapeutics