ISSN:
1432-1041
Keywords:
Bupranolol
;
Debrisoquine
;
Sparteine
;
CYP2D6
;
Polymorphism
;
high affinity
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary The β-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 μM, (+)-bupranolol was the most potent with an apparent Ki value of 0.55 μM, while the therapeutically used racemic bupranolol had an intermediate value of 0.88 μM. A 10 min pre-incubation of 5 μM 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 μM bupranolol, 5 μM 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 β-adrenoceptor blocker with the highest-known apparent affinity for CYP2D6. High affinity and rapid metabolism are infrequent combinations in enzymology.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00315393
