Verapamil decreases glucuronidase activity in the gut.
The present investigation addressed the role of verapamil for oral pharmacokinetics of morphine-6-beta-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 beta-glucuronidase was assessed using altered cleavage of the model substrate 4-methylumbelliferyl-beta-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 beta-glucuronidase from E. coli with an IC(50) of 30 microM, whereas no inhibition of the rat beta-glucuronidase from small intestine was seen. In conclusion, verapamil decreased intestinal deglucuronidation of M6G by inhibiting E. coli beta-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.
Lötsch
Jörn
J
Pharmazentrum Frankfurt, Department of Clinical Pharmacology, Johann Wolfgang Goethe-University Hospital, Theodor Stern Kai, D-60590 Frankfurt, Germany. j.loetsch@em.uni-frankfurt.de
Sperker
Bernhard
B
Kroemer
Heyo K
HK
Geisslinger
Gerd
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004347:Drug Interactions; D005966:Glucuronidase / Q000187:drug effects / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D023421:Models, Animal; D009022:Morphine Derivatives / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D014700:Verapamil; D005966:Glucuronidase