Involvement of CYP2C9 and UGT2B7 in the metabolism of zaltoprofen, a nonsteroidal anti-inflammatory drug, and its lack of clinically significant CYP inhibition potential.
OBJECTIVE
To identify the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) isoforms responsible for the formation of the primary metabolite(s) of zaltoprofen, and to predict possible drug interactions by investigating the inhibition of CYP isoforms in vitro.


METHODS
The metabolism of zaltoprofen was studied in vitro using recombinant CYP and UGT isoform cDNA-expression systems. The effects of selective isoform inhibitors on zaltoprofen metabolism were studied using human liver microsomes. The inhibitory effects of zaltoprofen on the metabolism of selective probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were also determined in human liver microsomes.


RESULTS
Zaltoprofen was extensively metabolized by CYP2C9 and UGT2B7. CYP2C9 catalysed sulphoxidation but not hydroxylation of zaltoprofen. In the human liver microsomal metabolism study, zaltoprofen metabolism was markedly inhibited by sulphaphenazole, a selective inhibitor of CYP2C9. In the drug interaction study, negligible inhibition (< 15%) of the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 was apparent at 5 micro g ml(-1), the maximum plasma concentration observed in humans after oral administration of an 80 mg zaltoprofen tablet. However, zaltoprofen inhibited CYP2C9 by 26% at 5 micro g ml(-1). At higher concentrations, zaltoprofen produced some inhibition of CYP2C9 (IC50 = 19.2 micro g ml(-1); 64.4 micro m) and CYP3A4 (IC50 = 53.9 micro g ml(-1); 181 micro m). The free drug concentrations in plasma (0.02 micro g ml(-1), 67.0 nm) at the Cmax of the clinically effective doses are much lower than the IC50 values corrected for the nonspecific binding ratio of zaltoprofen to microsomal protein (15.5 micro g ml(-1) for CYP3A4, 49.5 micro g ml(-1) for CYP3A4). Furthermore, the maximum free drug concentrations in the hepatic intracellular was calculated to be 0.068 micro g ml(-1) and the increase in the AUC in the presence of zaltoprofen was estimated to be only 0.4% for CYP2C9 substrates and 0.1% for CYP3A4 substrates, respectively.


CONCLUSIONS
Zaltoprofen is predominantly metabolized by CYP2C9 and UGT2B7, and is considered unlikely to cause significant drug interactions in vivo when coadministered with CYP substrates at clinically effective doses.
Furuta
Shigeru
S
Central Research Laboratories, ZERIA Pharmaceutical Co. Ltd, 2512-1 Oshikiri, Konan-machi, Osato-gun, Saitama, 360-0111, Japan. shigeru-furuta@zeria.co.jp
Akagawa
Nobuyoshi
N
Kamada
Emiko
E
Hiyama
Akio
A
Kawabata
Yoshihiro
Y
Kowata
Nobuhiko
N
Inaba
Atsuhiro
A
Matthews
Anne
A
Hall
Michael
M
Kurimoto
Tadashi
T
D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001578:Benzopyrans / Q000008:administration & dosage / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D065729:Cytochrome P-450 CYP2C9; D018076:DNA, Complementary / Q000378:metabolism; D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007536:Isomerism; D008862:Microsomes, Liver / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D018076:DNA, Complementary; D011422:Propionates; C043940:pyranoprofen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D014453:Glucuronosyltransferase