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.