INTERACTIONS OF BUPRANOLOL WITH THE POLYMORPHIC DEBRISOQUINE SPARTEINE MONOOXYGENASE (CYP2D6)

The beta-adrenoceptor blocker bupranolol turned out to be a competitiv e inhibitor of the polymorphic cytochrome P450 CYP2 D6 of which sparte ine is a substrate. There was stereo-selectivity of bupranolol involve d: (-)bupranolol was the weakest inhibitor with an apparent K(i) value of 1.32 muM, (+)-bupranolol was the most potent with an apparent Ki v alue of 0.55 muM, while the therapeutically used racemic bupranolol ha d an intermediate value of 0.88 muM. A 10 min pre-incubation of 5 muM bupranolol with the enzyme preparation prior to the addition of substr ate, reduced the inhibition of sparteine metabolism from 52 to about 2 5 %. This suggests that - during these inhibition studies - bupranolol was much more rapidly metabolized than was sparteine, so that the mea sured K(i) values must represent overestimates. The enzyme catalysing bupranolol metabolism was CYP2 D6: microsomes from a liver with the ge netic enzyme deficiency did not metabolize bupranolol; in microsomes f rom livers containing the enzyme and 10 muM bupranolol, 5 muM quinidin e caused a 72 % inhibition of bupranolol metabolism. Although our meth ods were not sufficiently sensitive to measure the K(m) of bupranolol directly, it is undoubtedly the beta-adrenoceptor blocker with the hig hest-known apparent affinity for CYP2 D6. High affinity and rapid meta bolism are infrequent combinations in enzymology.