caa a22 4500 477058116 CHVBK 20180405111352.0 cr unu---uuuuu 170330e19960101xx s 000 0 eng 10.1007/BF00226332 doi (NATIONALLICENCE)springer-10.1007/BF00226332 Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam [Elektronische Daten] [P. Bonnabry, T. Leemann, P. Dayer] Objective: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5′-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. Results: Lornoxicam 5′-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 μmol·l-1 and a Vmax of 2.6 nmol·h-1·mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5′-hydroxylation by CYP2C9 substrates and sulphaphenazole was comparable in all livers preparations, values predicted from their KM or Ki for CYP2C9 determined in separate studies assuming competitive inhibition. Sulphaphenazole competitively and completely inhibited lornoxicam 5′-hydroxylation (Ki=0.31 μmol·l-1) as well as lornoxicam clearance (Ki=0.33 μmol·l-1), partial metabolic clearance (fm)=0.95). Conclusion: 5′-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9. Springer-Verlag, 1996 Lornoxicam nationallicence CYP2C9 nationallicence cytochrome-P-450 nationallicence drug metabolism nationallicence NSAIDs nationallicence Bonnabry P. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut Leemann T. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut Dayer P. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut European Journal of Clinical Pharmacology Springer-Verlag 49/4(1996-01-01), 305-308 0031-6970 49:4<305 1996 49 228 https://doi.org/10.1007/BF00226332 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00226332 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bonnabry P. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut NATIONALLICENCE 700 1- Leemann T. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut NATIONALLICENCE 700 1- Dayer P. Division of Clinical Pharmacology and Pain Clinic, University Hospital, CH-1211, Geneva 14, Switzerland aut NATIONALLICENCE 773 0- European Journal of Clinical Pharmacology Springer-Verlag 49/4(1996-01-01), 305-308 0031-6970 49:4<305 1996 49 228 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer