The Glucuronidation of R- and S-Lorazepam: Human Liver Microsomal Kinetics, UDP-Glucuronosyltransferase Enzyme Selectivity, and Inhibition by Drugs

Abstract

The widely used hypnosedative-anxiolytic agent R,S-lorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. The present study characterized the kinetics of the separate R and S enantiomers of lorazepam by human liver microsomes (HLMs) and by a panel of recombinant human UDP-glucuronosyltransferase (UGT) enzymes. Respective mean K m and V max values for R-and S-lorazepam glucuronidation by HLM were 29 6 8.9 and 36 6 10 mM, and 7.4 6 1.9 and 10 6 3.8 pmol/min × mg. Microsomal intrinsic clearances were not significantly different, suggesting the in vivo clearances of R-and Slorazepam are likely to be similar. Both R-and S-lorazepam were glucuronidated by UGT2B4, 2B7, and 2B15, whereas R-lorazepam was additionally metabolized by the extrahepatic enzymes UGT1A7 and 1A10. Based on in vitro clearances and consideration of available in vivo and in vitro data, UGT2B15 is likely to play an important role in the glucuronidation of R-and S-lorazepam. However, the possible contribution of other enzymes and the low activities observed in vitro indicate that the lorazepam enantiomers are of limited use as substrate probes for UGT2B15. To identify potential drug-drug interactions, codeine, fluconazole, ketamine, ketoconazole, methadone, morphine, valproic acid, and zidovudine were screened as inhibitors of R-and S-lorazepam glucuronidation by HLM. In vitro-in vivo extrapolation suggested that, of these drugs, only ketoconazole had the potential to inhibit lorazepam clearance to a clinically significant extent.

Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

“…In addition, rifampin-mediated DDI via UGTs is common in many cases (9). Ketoconazole, a nonspecific inhibitor of CYP3A4, also can inhibit UGTs (10,11). DDI caused by the induction or inhibition of phase II enzyme is also of the great concern for both scientists and the pharmaceutical industry.…”

Pharmacokinetic Interactions between Valproic Acid and Lorazepam (PIVOtAL Study): A Review of Site-Specific Practices

“…12 In vitro studies in rat and human liver tissue have shown that valproic acid can decrease glucuronidation activity, resulting in an increase in the area under the plasma concentration-time curve (AUC) by 15% to 18%. 10,11 However, the reported values of the inhibitor constant for the inhibition of lorazepam glucuronidation by valproic acid are much greater than concentrations that are usually achieved in vivo. 11,13 This situation alludes to the limitations of in vitro UGT inhibition studies, given that the inhibitory effects may not occur in humans.…”

“…10,11 However, the reported values of the inhibitor constant for the inhibition of lorazepam glucuronidation by valproic acid are much greater than concentrations that are usually achieved in vivo. 11,13 This situation alludes to the limitations of in vitro UGT inhibition studies, given that the inhibitory effects may not occur in humans. 7 Theoretically, inhibition of lorazepam glucuronidation may prolong its sedative effects and pose potential safety concerns.…”

“…[6][7][8][9] Lorazepam is also extensively metabolized by the same UGT enzymes that are inhibited by valproic acid. 10,11 The proposed pharmacokinetic (PK) interaction between lorazepam and valproic acid is believed to be due to the inhibition of glucuronidation, presumably by direct inhibition of UGT enzymes by valproic acid. 12 In vitro studies in rat and human liver tissue have shown that valproic acid can decrease glucuronidation activity, resulting in an increase in the area under the plasma concentration-time curve (AUC) by 15% to 18%.…”

Efectos de los inductores antiepilépticos en la neuropsicofarmacología: una cuestión ignorada. Parte II: cuestiones farmacológicas y comprensión adicional

“…En la literatura sobre neuropsicofarmacología existe un consenso definitivo en cuanto a que el AVP inhibe la glucuronidación de 2 fármacos, la lamotrigina 74,80,82 y el lorazepam 74,83 . Estos son metabolizados principalmente por las UGT, pero como no existe acuerdo sobre qué UGT es inhibida por el AVP, no puede explicarse los mecanismos de dicha inhibición.…”