The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

Lennard,; Jackson, Paul R.; Freestone, S.; Tucker, GT; Ramsay, LE; Woods, Helen Buckley

doi:10.1111/j.1365-2125.1984.tb02403.x

Cited by 62 publications

(24 citation statements)

References 18 publications

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“…The fact that propranolol was shown to be sensitive towards CYP2D6 inhibitors (propafenone and quinidine; studies in Caucasians) is in disagreement with the two genetic studies that reported no influence of CYP2D6 activity on the exposure of propranolol in Caucasians (table 3) [68,69]. Propafenone is additionally an inhibitor of CYP1A2 (table 5), an enzyme also involved in the metabolism of propranolol, and the influence of this inhibitor could be explained by changed CYP1A2 metabolism.…”

Section: Relative Exposure Of Cvds With Cyp2d6 Inhibitorscontrasting

confidence: 41%

“…The clinical implications for patients of these findings have not been outlined, but an approximately 50-100% difference in exposure ('dose') must empirically be considered as relevant. For propranolol (ß 1/2 -receptor antagonist), it is surprising that the exposure was reported to be unaffected by CYP2D6 activity in Caucasians (PMs versus EMs) [68,69], whereas a 2-fold higher level was observed in Chinese IMs [70,71]. This might indicate that another eliminating pathway(s) than CYP2D6 (e.g.…”

Section: Cyp2d6 Genetics and Variability In Exposure Of Cvdsmentioning

confidence: 89%

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Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Molden¹

2004

Heart Drug

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Cytochrome P450 (CYP) enzymes play an important role in the turnover of more than 50 cardiovascular drugs (CVDs). Variable CYP activities due to genetic polymorphism or drug interactions are important sources of variability in systemic exposure of many of these drugs. The therapeutic implications are in most cases an increased response (effect/side effects) in patients with genetically determined decreased/deficient metabolic activity or during concurrent use of CYP inhibitors. Special attention with regard to safety should be paid to several coumarin-type anticoagulants, antiarrhythmics, β-receptor antagonists and HMG-CoA reductase inhibitors (statins). Prevention of potential clinical problems associated with CYP variability is easily achieved using equally effective therapeutic alternatives that are not dependent on CYP metabolism. However, if ‘CYP sensitive’ CVDs are either the preferred or only therapeutic alternatives, restrictive use of inhibitors is advisable, whereas patient genotyping prior to treatment might be a helpful tool to apply rational (individual) doses for certain agents.

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Section: Relative Exposure Of Cvds With Cyp2d6 Inhibitorscontrasting

confidence: 41%

Section: Cyp2d6 Genetics and Variability In Exposure Of Cvdsmentioning

confidence: 89%

Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Molden¹

2004

Heart Drug

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“…Ring hydroxylation to form 4-hydroxypropranolol (4HP) is impaired in poor metabolisers (PM) of debrisoquine (Lennard et al, 1984;Raghuram et al, 1984). In this phenotype, P4501ID6 is absent as a result of splicing errors during transcription of the gene (Gonzalez et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Otton

Lennard

et al. 1990

Brit J Clinical Pharma

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1 Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-4501ID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2 In the presence of NADPH and oxygen 4-and 5-hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N-desisopropylation. R(+)-propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N-desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N-desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3 Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4-and 5-hydroxylation occurred in microsomes from the EM livers only and b) side-chain oxidation was not observed under these conditions in either PM or EM livers. 4 Using cumene hydroperoxide to support the reactions, the 4-hydroxylation of propranolol showed little enantioselectivity, whereas S(-)-propranolol was 5-hydroxylated about twice as fast as the R(+)-enantiomer. There were highly significant correlations between the rates of 4-and 5-hydroxylation of R(+)-propranolol (r = 0.96, P < 0.001, n = 7 livers) and of S(-)-propranolol (r = 0.98, P < 0.001). Both oxidations were described by single-site Michaelis-Menten kinetics. 5 The findings suggest that P4501ID6 is involved in both the 4-and 5-hydroxylations of propranolol, but that these metabolites can also be formed by other P450 isoenzymes. It is confirmed that P450IID6 does not contribute to the N-desisopropylation of propranolol. Furthermore, the finding that mephenytoin did not inhibit the appearance of this metabolite is not consistent with the results of in vivo studies suggesting the involvement of the same enzyme in the side-chain oxidation of propranolol and the 4-hydroxylation of mephenytoin.

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“…In vitro [2] and in vivo studies [3] have suggested that aromatic ring 4-hydroxylation of the drug cosegregates with debrisoquine 4-hydroxylase (CYP2D6) activity, which exhibits a major genetic polymorphism in various ethnic groups [4,5]. The side-chain oxidation of propranolol has been suggested to cosegregate with S-mephenytoin 4'-hydroxylase (CYP2C19) activity [6] which also exhibits a marked genetic polymorphism [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers—N‐desisopropylation is mediated mainly by CYP1A2.

Yoshimoto

Echizen

Chiba

et al. 1995

Brit J Clinical Pharma

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1 Studies using human liver microsomes and six recombinant human CYP isoforms (i.e. CYP1A2, 2A6, 2B6, 2D6, 2E1 and 3A4) were performed to identify the cytochrome P450 (CYP) isoform(s) involved in the ring 4-hydroxylation and sidechain N-desisopropylation of propranolol enantiomers in humans. 2 a-Naphthoflavone and 7-ethoxyresorufin (selective inhibitors of CYPlAl/2) inhibited the N-desisopropylation of R-and S-propranolol by human liver microsomes by 20 and 40%, respectively, while quinidine (a selective inhibitor of CYP2D6) abolished the 4-hydroxylation of both propranolol enantiomers almost completely. In contrast, sulphaphenazole (CYP2C8/9 inhibitor), S-mephenytoin (CYP2C19 inhibitor), troleandomycin (CYP3A3/4 inhibitor) and diethyldithiocarbamate (CYP2E1 inhibitor) elicited only weak inhibitory effects on propranolol metabolism via the two measured metabolic pathways. 3 Significant (P < 0.01) correlations were observed between the microsomal N-desisopropylation of both propranolol enantiomers and that for the O-deethylation of phenacetin among the 11 different human liver microsome samples (r = 0.98 and 0.77 for R-and S-propranolol, respectively). A marginally significant (r = 0.60, P L' 0.05) correlation was also observed between N-desisopropylation of S-, but not of R-propranolol and the 4'-hydroxylation of S-mephenytoin. No significant correlations were observed between the N-desisopropylation of propranolol enantiomers and the 2-hydroxylation of desipramine, the hydroxylation of tolbutamide or the 60-hydroxylation of testosterone.4 Significant (P <0.01) correlations were observed between the microsomal 4-hydroxylation of R-and S-propranolol and the 2-hydroxylation of desipramine (r = 0.85 and 0.98, respectively). A weak (r = 0.66), albeit significant (P < 0.05), correlation was observed between the 4-hydroxylation of R-, but not of S-propranolol and the hydroxylation of tolbutamide. No significant correlations were observed between the 4-hydroxylation of propranolol enantiomers and the oxidation of other substrates for CYP1A2, 2C19, and 3A3/4. 5 Recombinant human CYP1A2 and CYP2D6 exhibited comparable catalytic activity with respect to the N-desisopropylation of both propranolol enantiomers; only expressed CYP2D6 exhibited a marked catalytic activity with respect to the 4-hydroxylation of both propranolol enantiomers. 6 We conclude that the side-chain N-desisopropylation of both propranolol enantiomers is mediated mainly by the CYPIA subfamily and to some extent by CYP2D6, whereas the ring 4-hydroxylation of the enantiomers is mediated almost exclusively by CYP2D6. The contribution of S-mephenytoin 4'-hydroxylase (CYP2C19) to the N-desisopropylation of propranolol enantiomers appears to be of negligible importance in human liver microsomes.

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The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

Cited by 62 publications

References 18 publications

Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers—N‐desisopropylation is mediated mainly by CYP1A2.

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