Vol. 282, Issue 3, 1465-1472, 1997

Involvement of Human CYP1A Isoenzymes in the Metabolism and Drug Interactions of Riluzole In Vitro¹

Ger-Jan Sanderink, Bruno Bournique, Jeffrey Stevens, Martine Petry and Michel Martinet

Drug Metabolism and Pharmacokinetics Department, Rhône-Poulenc Rorer Research and Development, Antony (G.-J.S.) and Vitry/Alfortville (B.B., M.P., M.M.), France, and Collegeville, Pennsylvania (J.S.)

Cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes involved in riluzole oxidation and glucuronidation were characterized in (1) kinetic studies with human hepatic microsomes and isoenzyme-selective probes and (2) metabolic studies with genetically expressed human CYP isoenzymes from transfected B-lymphoblastoid and yeast cells. In vitro incubation of [¹⁴C]riluzole (15 µM) with human hepatic microsomes and NADPH or UDPGA cofactors resulted in formation of N-hydroxyriluzole (K_m = 30 µM) or an unidentified glucuroconjugate (K_m = 118 µM). Human microsomal riluzole N-hydroxylation was most strongly inhibited by the CYP1A2 inhibitor -naphthoflavone (IC₅₀ = 0.42 µM). Human CYP1A2-expressing yeast microsomes generated N-hydroxyriluzole, whereas human CYP1A1-expressing yeast microsomes generated N-hydroxyriluzole, two additional hydroxylated derivatives and an O-dealkylated derivative. CYP1A2 was the only genetically expressed human P450 isoenzyme in B-lymphoblastoid microsomes to metabolize riluzole. Riluzole glucuronidation was inhibited most potently by propofol, a substrate for the human hepatic UGT HP4 (UGT1.8/9) isoenzyme. In vitro, human hepatic microsomal hydroxylation of riluzole (15 µM) was weakly inhibited by amitriptyline, diclofenac, diazepam, nicergoline, clomipramine, imipramine, quinine and enoxacin (IC₅₀  200-500 µM) and cimetidine (IC₅₀ = 940 µM). Riluzole (1 and 10 µM) produced a weak, concentration-dependent inhibition of CYP1A2 activity and showed competitive inhibition of methoxyresorufin O-demethylase. Thus, riluzole is predominantly metabolized by CYP1A2 in human hepatic microsomes to N-hydroxyriluzole; extrahepatic CYP1A1 can also be responsible for the formation of several other metabolites. Direct glucuronidation is a relatively minor metabolic route. In vivo, riluzole is unlikely to exhibit significant pharmacokinetic drug interaction with coadministered drugs that undergo phase I metabolism.