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  • 1
    Electronic Resource
    Electronic Resource
    Oxidation phenotype and the metabolism and action of beta-blockers (1985)
    Springer
    Journal of molecular medicine 63 (1985), S. 285-292 
    Details
    ISSN: 1432-1440
    Keywords: Oxidation Phenotype ; Debrisoquine ; Beta-Blockers ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Variability in response to some drugs such as debrisoquine can be attributed to genetic polymorphism of their oxidative metabolism. Most beta-adrenoceptor antagonists (beta-blockers) are extensively metabolised via oxidative routes. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers of debrisoquine (PM) have claimed that their oxidation is under polymorphic control. Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The PM phenotype is associated with an increased drug bioavailability, a prolongation of elimination half-life and more intense and sustained betablockade. Phenotypic differences were also noted in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro work has identified some of the metabolic pathways which are subject to the defect, namely, the α-hydroxylation and the 0-dealkylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lowered in PM subjects. The clinical significance of impaired elimination of beta-blockers is unclear. If standard doses of beta-blockers are used in PM subjects, they may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01731972
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Variability of plasma drug concentrations — A reply (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 659-659 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; drug adjustment ; elimination ; poor metaboliser ; drug oxidation ; drug reaction monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543508
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Polymorphic metabolism of metoprolol: Clinical studies (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 85-88 
    Details
    ISSN: 1432-1041
    Keywords: debrisoquine oxidation ; metoprolol metabolism ; oxidation phenotype ; β-blockade ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After a single 200 mg oral dose of metoprolol tartrate the mean metoprolol AUC was found to be six-fold higher in poor metabolizers (PMs) of debrisoquine than in extensive metabolizers (EMs). This was associated with impaired metabolic clearance via α-hydroxylation and O-dealkylation. A population study (n=143) has shown a bimodal distribution in the ratio of metoprolol: α-hydroxymetoprolol recovered in urine which was correlated highly with the debrisoquine metabolic ratio. Nine per cent of the population were PMs. Plasma metoprolol concentrations three hours after a 100 mg oral dose of metoprolol were greater than 200 ng/ml in PMs but were lower than this in most EMs. This dose of metoprolol given once daily provided a clinically significant reduction (16%) in exercise heart rate in PMs after 24 hours. EMs require conventional doses (100 mg b.d.) to achieve the same degree of β-blockade. Preliminary data from family studies support the view that the defect in metoprolol oxidation is inherited. In 12 hypertensive patients who were EMs we compared the β-blocking activity and antihypertensive effect of chronic treatment with metoprolol 200 mg once daily (conventional and long-acting formulations), with those of atenolol 100 mg once daily and placebo. The effects of all active preparations were similar at 3.5 hours but atenolol was superior to all metoprolol formulations at 24 hours after dosing. It is concluded that for the majority of patients metoprolol should be prescribed twice daily when using currently available dosage forms. Relationships between oxidation phenotype and side-effects should be examined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543716
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  • 4
    Electronic Resource
    Electronic Resource
    Time-dependent kinetics of lignocaine in the isolated perfused rat liver (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 165-182 
    Details
    ISSN: 1573-8744
    Keywords: zlignocaine ; lidocaine ; time-dependent kinetics ; isolated perfused rat liver ; nonlinear hepatic uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The kinetics of lignocaine have been investigated in the isolated perfused rat liver preparation. After a low dose (0.3 mg) the drug was eliminated according to first-order kinetics, but after higher doses (7.5, 15.0 mg) and multiple doses (3×1.5 mg at 15 min intervals), nonlinear kinetics were observed, which appeared to show time dependence. This was not due to deterioration of the preparation nor was there any evidence of a hepatotoxic effect of lignocaine. The kinetics of lignocaine were also found to be sex-dependent since it was eliminated at a faster rate by livers from male rats compared to those from female rats. Exogenous MEGX (7.5 mg), the mono-N-deethylated metabolite of lignocaine, inhibited the elimination of parent drug (1.5 mg dose). However, evidence was obtained suggesting that a direct effect of this and other end-product metabolites may not be responsible for the observed changes in lignocaine kinetics with time when the compounds are produced endogenously. Studies of the hepatic binding of lignocaine in the preparation showed the presence of high affinity-low capacity and low affinity-high capacity binding sites, which may be the enzymes responsible for aromatic hydroxylation and N-deethylation of the drug, respectively. Further experiments supported the view that an intermediate product of lignocaine, related to the N-deethylation pathway, might be inhibiting its further metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061847
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    Paper (German National Licenses)
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