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CHARACTERIZATION OF AFLOQUALONE N-GLUCURONIDATION: SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM(S)

Exploratory Toxicology & DMPK Research Laboratories, Tanabe Seiyaku Co., LTD., Saitama, Japan

Afloqualone (AFQ) is one of the centrally acting muscle relaxants. AFQ N-glucuronide is the most abundant metabolite in human urine when administered orally, whereas it was not detected in the urine when administered to rats, dogs, and monkeys. Species differences in AFQ N-glucuronidation were investigated with liver microsomes obtained from humans and experimental animals. The kinetics of AFQ N-glucuronidation in human liver microsomes showed a typical Michaelis-Menten plot. The K_m and V_max values accounted for 2019 ± 85.9 µM and 871.2 ± 17.9 pmol/min/mg protein, respectively. The V_max and intrinsic clearance (CL_int) values of AFQ N-glucuronidation in human liver were approximately 4- to 10-fold and 2- to 4-fold higher than those in rat, dog, and monkey, respectively. Among 12 recombinant human UDP-glucuronosyltransferase (UGT) isoforms, both UGT1A4 and UGT1A3 exhibited high AFQ N-glucuronosyltransferase activities. The K_m value of AFQ N-glucuronidation in recombinant UGT1A4 microsomes was very close to that in human liver microsomes. The formation of AFQ N-glucuronidation by human liver, jejunum, and recombinant UGT1A4 microsomes was effectively inhibited by trifluoperazine, a known specific substrate for UGT1A4. The AFQ N-glucuronidation activities in seven human liver microsomes were significantly correlated with trifluoperazine N-glucuronidation activities (r² = 0.798, p < 0.01). In contrast, the K_m value of AFQ N-glucuronidation in recombinant UGT1A3 microsomes was relatively close to that in human jejunum microsomes. These results demonstrate that AFQ N-glucuronidation in human is mainly catalyzed by UGT1A4 in the liver and by UGT1A3, as well as UGT1A4 in the intestine.

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