Glucuronidation of propranolol by dog liver microsomes. Effects of enantiomeric inhibition and detergent treatment on stereoselectivity.
The diastereomeric glucuronides of (R)- and (S)-propranolol [(R)-PG and (S)-PG] formed by incubating the racemic drug with dog liver microsomes were separated and quantitated chromatographically. Conjugation occurred stereoselectively with 3- to 4-fold more (S)-PG than (R)-PG produced. The values for the apparent Km were 1.0 and 1.7 mM, and those of the Vmax were 6.4 and 25 nmol/min/mg protein for (R)- and (S)-propranolol, respectively. Stereoselectivity was lower in parallel incubations conducted with the separate enantiomers than in incubates with the racemic substrate. The S enantiomer was found to be a noncompetitive inhibitor of (R)-PG formation, with a Ki of 1.8 mM. (S)-PG did not inhibit (R)-PG formation when added to incubates and (R)-propranolol did not inhibit the formation of (S)-PG. The presence of sodium cholate and Brij 35 stimulated glucuronidation by 60 and 120%, respectively, but did not affect the stereoselectivity even at concentrations high enough to inhibit conjugation. On the contrary, Triton X-100 and Emulgen 911 were inhibitory and produced a decrease in stereoselectivity; the magnitude of these effects increased with increasing detergent concentration.
D000818:Animals; D003902:Detergents / Q000494:pharmacology*; D004285:Dogs; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013501:Surface-Active Agents / Q000494:pharmacology*
D003902:Detergents; D013501:Surface-Active Agents; C022056:propranolol glucuronide; D011433:Propranolol; D014453:Glucuronosyltransferase