Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam

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Abstract
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.

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