Interactions of bupranolol with the polymorphic debrisoquine/sparteine monooxygenase (CYP2D6)

Abstract

The beta-adrenoceptor blocker bupranolol turned out to be a competitive inhibitor of the polymorphic cytochrome P450 CYP2D6 of which sparteine is a substrate. There was stereo-selectivity of bupranolol involved: (-)-bupranolol was the weakest inhibitor with an apparent Ki value of 1.32 microM, (+)-bupranolol was the most potent with an apparent Ki value of 0.55 microM, while the therapeutically used racemic bupranolol had an intermediate value of 0.88 microM. A 10 min pre-incubation of 5 microM bupranolol with the enzyme preparation prior to the addition of substrate, reduced the inhibition of sparteine metabolism from 52 to about 25%. This suggests that--during these inhibition studies--bupranolol was much more rapidly metabolized than was sparteine, so that the measured Ki values must represent overestimates. The enzyme catalysing bupranolol metabolism was CYP2D6: microsomes from a liver with the genetic enzyme deficiency did not metabolize bupranolol; in microsomes from livers containing the enzyme and 10 microM bupranolol, 5 microM quinidine caused a 72% inhibition of bupranolol metabolism. Although our methods were not sufficiently sensitive to measure the Km of bupranolol directly, it is undoubtedly the beta-adrenoceptor blocker with the highest-known apparent affinity for CYP2D6. High affinity and rapid metabolism are infrequent combinations in enzymology.