The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans

@article{Capon1996TheIO,
  title={The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans},
  author={Debra Ann. Capon and Felix Bochner and Nip Kerry and Gerd Mikus and Cath Danz and Andrew Alexander Somogyi},
  journal={Clinical Pharmacology \& Therapeutics},
  year={1996},
  volume={60}
}
We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan. 
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone
TLDR
The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine.
Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs.
This review highlights the present knowledge on the CYP2D6 (sparteine/debrisoquine) and the CYP2C19 (mephenytoin) polymorphisms. The relevant mutations at genomic level affecting protein expression
The antitussive effect of dextromethorphan in relation to CYP2D6 activity.
TLDR
Although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.
Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites.
TLDR
A single time point serum PPF-MR approach is a useful tool to identify PMs and CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites.
Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers.
TLDR
Six adults phenotyped as either extensive or poor metabolizers for cytochrome P450 (CYP) 2D6 were given a 10-mg oral dose of methylphenidate (MPH) on two separate occasions with and without quinidine, a potent CYP2D6 inhibitor, suggesting a lack of involvement of CYP1D6 in the metabolism of MPH.
GENES BY POPULATION PHARMACOKINETICS OF DEXTROMETHORPHAN
The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and
Evaluation of dextromethorphan metabolism using hepatocytes from CYP2D6 poor and extensive metabolizers.
TLDR
Cryopreserved human hepatocytes of CYP2D6 poor metabolizer (PM) for the estimation of the metabolism in PM using dextromethorphan (DEX) as the probe drug for CYP1D6 substrate reflected the clinical data, and results would suggest that CYP 2D6 PM hepatocytes could be a good in vitro tool for estimating CYP3A4/5 PM pharmacokinetics.
Dextromethorphan and debrisoquine metabolism and polymorphism of the gene for cytochrome P450 isozyme 2D50 in Thoroughbreds.
TLDR
It is suggested that CYP2D50 is polymorphic and that the disposition of the probe drug varies markedly in horses, and the polymorphisms may be related to rates of drug metabolism.
Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration.
TLDR
Dextromethorphan was found to be eliminated from the urine predominately as the O-demethylated metabolite, dextrorphan, and several additional metabolites including several novel hydroxy-dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms.
Induction of CYP2D6 in pregnancy
TLDR
The results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy and indicate an increase in CYP 2D6 activity during pregnancy, which may be caused by an induction of the cytochrome P4502D 6 enzyme.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 72 REFERENCES
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.
Molecular genetics of the debrisoquin‐sparteine polymorphism
Clinical Pharmacology and Therapeutics (1991) 50, 233–238; doi:10.1038/clpt.1991.131
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
Deficient metabolism of debrisoquine and sparteine
TLDR
Evidence is reported to indicate that the genetic defect in the metabolism of sparteine and debrisoquine is not a generalized deficiency of drug oxidation or of the cytochrome P450 system.
Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism.
TLDR
The hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation was tested and it was found that in extensive metabolizers,Quinidine did not changeEncainide disposition kinetics and neither encainides alone nor encainid plus quinazine significantly altered electrocardiographic intervals.
The genetic polymorphism of sparteine metabolism.
TLDR
The data indicate that the basis of the differences in oxidative capacity between EM and PM subjects is more likely to be due to a variant isozyme with defective catalytic properties than to a decreased amount of the isozyme.
Dextromethorphan: Enhancing its systemic availability by way of low‐dose quinidine‐mediated inhibition of cytochrome P4502D6
TLDR
It is estimated that brain dextromethorphan concentrations of 1.0 to 10 µg/gm may be attainable in humans by inhibition of cytochrome P4502D6 activity with quinidine.
Single-dose quinidine treatment inhibits mexiletine oxidation in extensive metabolizers of debrisoquine.
TLDR
It is concluded that pretreatment with a very low dose of quinidine inhibits markedly the elimination of both major mex toiletine metabolites (PHM and HMM) and likely decreases the overall elimination of mexiletine.
Hypotensive response to debrisoquine and hydroxylation phenotype.
TLDR
It is concluded that the genetic factor which controls the metabolism of debrisoquine is also largely responsible for the differences in response seen between the two debrisquine hydroxylator phenotypes.
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.
...
1
2
3
4
5
...