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

@article{Pressacco2004InteractionsOB,
  title={Interactions of bupranolol with the polymorphic debrisoquine/sparteine monooxygenase (CYP2D6)},
  author={Josie Pressacco and R. Muller and Werner Kalow},
  journal={European Journal of Clinical Pharmacology},
  year={2004},
  volume={45},
  pages={261-264}
}
SummaryThe 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… 
1 Citations
Synthesis and application of bimetallic chiral [Co(salen)]‐type complexes: a new catalytic approach to synthesis of optically pure β‐blockers via kinetic resolution of epichlorohydrin
A series of bimetallic chiral [Co(salen)]-type complexes were successfully applied for the synthesis of optically pure β-blockers via phenolic kinetic resolution (PKR) of racemic epichlorohydrin

References

SHOWING 1-10 OF 28 REFERENCES
Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs.
TLDR
In vitro competitive inhibition of sparteine oxidation by a drug indicates that this drug is capable of occupying the same enzymatic site as spartanine and may mean that the competing drug is also metabolized at that site and thereby subject to the same genetic variation as spartein's oxidation.
Evidence in humans for variant allozymes of the nondeficient sparteine/debrisoquine monooxygenase (P45OIID 1) in vitro.
TLDR
The different ratio of these two dehydrosparteines, which was found at low and high substrate concentrations, suggests that the reactions producing the primary metabolite are different between the quinidine-sensitive and -insensitive enzymes.
Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6.
TLDR
Data indicate that P450IID1 is expressed centrally and is similar, at the functional and molecular levels, to the human hepatic P450 IID1 enzyme, which may possibly lead to differences in drug response and toxicity.
The genetic polymorphism of debrisoquine/sparteine metabolism--clinical aspects.
TLDR
The therapeutic implications for each of the classes of drugs affected by this genetic polymorphism in drug metabolism are discussed and it is emphasized that it is difficult to attain therapeutic plasma concentrations for some drugs in high activity extensive metabolizers.
Sparteine metabolism capacity in human liver: structural variants of human P450IID6 as assessed by immunochemistry.
TLDR
An antibody raised against rat P450dbl was used to examine the heterogeneity of the human enzyme involved in the sparteine/debrisoquine polymorphism and variation in inhibition by this antibody reflected the amount of P450IID6 protein.
The role of lipophilicity in the inhibition of polymorphic cytochrome P450IID6 oxidation by beta-blocking agents in vitro.
TLDR
Lipophilicity is a key predictor of the affinity of beta-blocking drugs for cytochrome P450IID6 and of their potential to cause specific competitive drug interactions, but more complex structural factors appear to be important as well.
Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics.
TLDR
There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and the area under the plasma concentration time curve (AUC) for timolol and the mean degree of beta-adrenoceptor blockade was significantly greater in the poor metabolisers than in the extensive metaboliser 24 h after dosing with timoll.
The genetic control of bufuralol metabolism in man.
TLDR
Determination of the plasma metabolic ratio in the family of this subject and in a larger population confirmed that aliphatic hydroxylation of bufuralol is under polymorphic control.
Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine‐type polymorphism of drug oxidation
TLDR
Microsomes of one individual identified as poor metabolizer of debrisoquine in vivo showed reduction of carbinol formation to 1·97 nmol mg‐ h‐1, and Mixing his microsomes with those of an extensive metabolizer resulted in additive formation ofcarbinol excluding mediation of the defect by a soluble inhibitor.
Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs.
Testing for competitive inhibition of sparteine oxidation in the 9000 x g supernatant fraction from human liver provides an in vitro means to identify drugs which can bind to the same form of
...
1
2
3
...