Human liver morphine UDP‐glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam

Abstract

1 Morphine uridine diphosphate glucuronyl transferase (UDP-GT) was studied in human liver microsomes. The (-)-and (+)-morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver. 2 The overall glucuronidation of (+ )-morphine was higher than that of (-)-morphine. The morphine congeners tested, potently inhibited the formation of (-)-morphine-3-glucuronide ((-)-M3G), except for normorphine and codeine. The formation of ( + )-morphine-6-glucuronide ((+ )-M6G) was potently inhibited by only dextromethorphan and (+)naloxone. All drugs except normorphine inhibited the formation of(+)-M3G by 18-50%. 3 The metabolism of (-)-morphine to (-)-M3G was more sensitive to oxazepam inhibition than the formation of ( + )-M3G from (+ )-morphine in the rat liver. 4 The glucuronidation of natural morphine is subject to in vitro interaction with oxazepam and several opiate drugs. Our study supports the theory of more than one type of UDP-GT being involved in morphine glucuronidation.

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

“…The formation kinetics (K m and V max ) for both M3G (1.1 mM and 555 nmol mg −1 protein h −1 , respectively) and M6G (1.1 mM and 115 nmol mg −1 protein h −1 , respectively) were comparable to previously reported values of 0.9-5.2 mM and 56-402 nmol mg −1 protein h −1 for M3G and 0.5-1.2 mM and 8-89 nmol mg −1 protein h −1 for M6G [11,12,14].…”

“…In addition, K i values for M3G inhibition were significantly greater than for M6G for both (R)-methadone (P = 0.017, 128; 55, 202 µM) and (S)-methadone (P = 0.026, 75; 22, 128 µM). [11,12,14].…”

“…Comparison between these studies is further complicated due to variation in incubation conditions and the method of microsome activation. The mean single enzyme K m and V max values reported for M3G formation range from 0.9 to 5.2 m M and 56 to 402 nmol mg − 1 protein h − 1 , respectively, and for M6G from 0.51 to 1.23 m M and 7.8 to 88.8 nmol mg − 1 protein h − 1 , respectively [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17].…”

“…Although the in vitro glucuronidation of morphine has been widely studied [10][11][12][13][14], few studies have investigated the simultaneous formation of both metabolites in human liver microsomes. Comparison between these studies is further complicated due to variation in incubation conditions and the method of microsome activation.…”

“…M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17].…”