Verapamil decreases glucuronidase activity in the gut

The present investigation addressed the role of verapamil for oral pharmacokinetics of morphine-6-β-glucuronide (M6G). Male Sprague–Dawley rats received 62.5 mg kg−1 M6G-dihydrate orally w/wo pre-treatment with 70 mg kg−1 verapamil. Intravenous M6G (3.9 mg kg−1 ) and oral morphine (52.7 mg kg−1 morphine–hydrochloride) were also employed. Oral bioavailability of M6G and the fraction of M6G deglucuronidated to morphine were estimated from areas under the plasma-concentration vs. time curves (AUC) of morphine and its glucuronides. As initial results pointed towards inhibition of glucuronidases by verapamil, its capability to specifically inhibit E. coli and/or rat intestinal β-glucuronidase was assessed using altered cleavage of the model substrate 4-methylumbelliferyl-β-d-glucuronide (MUG). Oral bioavailability of M6G was 2.1%; 13% of oral M6G was deglucuronidated to morphine. Co-administration of verapamil did not increase the AUC of M6G. AUCs of morphine and morphine-3-glucuronide were smaller in the verapamil group than in controls. Verapamil co-administration decreased the fraction of M6G deglucuronidated to morphine to 4.6%. In vitro experiments provided evidence that verapamil inhibits β-glucuronidase from E. coli with an ic50 of 30 μM, whereas no inhibition of the rat β-glucuronidase from small intestine was seen. In conclusion, verapamil decreased intestinal deglucuronidation of M6G by inhibiting E. coli β-glucuronidase. This indicates that verapamil is not suited as P-gp inhibitor in experiments involving glucuronides. An increase in the intestinal absorption of M6G due to P-gp-inhibition was not observed at the verapamil dose studied. [Copyright &y& Elsevier]