PT  - JOURNAL ARTICLE
AU  - Ger-Jan Sanderink
AU  - Bruno Bournique
AU  - Jeffrey Stevens
AU  - Martine Petry
AU  - Michel Martinet
TI  - Involvement of Human CYP1A Isoenzymes in the Metabolism and Drug Interactions of Riluzole <em>In Vitro
</em>
DP  - 1997 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1465--1472
VI  - 282
IP  - 3
4099  - http://jpet.aspetjournals.org/content/282/3/1465.short
4100  - http://jpet.aspetjournals.org/content/282/3/1465.full
SO  - J Pharmacol Exp Ther1997 Sep 01; 282
AB  - 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 (Km = 30 μM) or an unidentified glucuroconjugate (Km = 118 μM). Human microsomal riluzole N-hydroxylation was most strongly inhibited by the CYP1A2 inhibitor α-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. The American Society for Pharmacology and Experimental Therapeutics