title: In vitro metabolism of the specific endothelin-A receptor antagonist ZD4054 and clinical drug interactions between ZD4054 and rifampicin or itraconazole in healthy male volunteers.
abstract: ZD4054 is an oral specific endothelin-A receptor antagonist in development for the treatment of hormone-resistant prostate cancer. Both renal and metabolic processes contribute to its overall clearance. Two preclinical in vitro studies investigated the metabolism of ZD4054 using human liver microsomes, individual cytochrome P450 (CYP) isozymes, and flavin-containing monooxygenase isoforms. Two Phase I open-label crossover volunteer studies subsequently investigated in vivo drug interactions between ZD4054 and the CYP450 inducer rifampicin or CYP3A4 inhibitor itraconazole. The most abundant metabolite produced in in vitro incubations accounted for 12.8% of radioactivity after ZD4054 was incubated with CYP3A4. No significant flavin-containing monooxygenase metabolism of ZD4054 was observed. In the in vivo studies, rifampicin co-administration reduced the area under the concentration-time curve and maximum plasma concentration of ZD4054 by 68% and 29%, respectively, whilst co-administration with itraconazole was associated with an increase in ZD4054 area under the curve of approximately 28%. While co-administration of CYP450 inducers might be associated with reduced efficacy of ZD4054, dose reduction is unlikely to be required with concomitant administration of CYP3A4 inhibitors.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK. Helen.Swaisland@astrazeneca.com
authors.forename: H C
authors.initials: HC
authors.lastname: Swaisland
authors.forename: S D
authors.initials: SD
authors.lastname: Oliver
authors.forename: T
authors.initials: T
authors.lastname: Morris
authors.forename: H K
authors.initials: HK
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Bakhtyari
authors.forename: A
authors.initials: A
authors.lastname: Mackey
authors.forename: A D
authors.initials: AD
authors.lastname: McCormick
authors.forename: D
authors.initials: D
authors.lastname: Slamon
authors.forename: J A
authors.initials: JA
authors.lastname: Hargreaves
authors.forename: A
authors.initials: A
authors.lastname: Millar
authors.forename: M T
authors.initials: MT
authors.lastname: Taboada
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003710:Demography; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006262:Health; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010105:Oxygenases / Q000378:metabolism; D011759:Pyrrolidines / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; C511404:ZD4054; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D012293:Rifampin