Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.

Abstract

1 The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. 2 The loglo metoprolol to a-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P < 0.001).3 The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. 4 The major urinary metabolite of metoprolol metabolism was H117-04, the endproduct of O-dealkylation. The distribution of the log1o metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P < 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. 5 These results indicate that both the a-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. 6 Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 7 In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population.

“…Caution should be exercised in interpreting our results, because the phenotyping criteria used were those derived from a Caucasian population (McGourty et al, 1985;Evans et al, 1980;Eichelbaum et al, 1986). There is no evidence that the antimodes of the three test probes are the same for both ethnic groups.…”

“…with fluorescence detection as described by Horai et al (1988b). Metoprolol oxidation capacity was expressed as the urinary metoprolol to HM (M/HM) ratio (referred to as the metabolic ratio: MR), and a PM phenotype was defined as one with a urinary M/HM ratio greater than 12.6 (log1o M/HM > 1.10) (McGourty et al, 1985).…”

“…Metoprolol oxidation capacity has also been shown to correlate with that of debrisoquine (McGourty et al, 1985) and sparteine (Eichelbaum et al, 1986). However, crossover studies comparing the capacity of subjects to metabolise debrisoquine and sparteine have given conflicting results (Evans et al, 1983;Woolhouse et al, 1985).…”

Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices.

“…Our studies have concentrated upon 3-adrenoceptor antagonists, particularly metoprolol, which, like debrisoquine, undergoes extensive first-pass hepatic metabolism (Lennard et al, 1982;McGourty et al, 1985). In this case, the measurement of urinary drug:metabolite ratios also proved to be a sensitive and convenient method Correspondence: Dr G. T. Tucker, University Department of Therapeutics, The Royal Hallamshire Hospital, Sheffield S10 2JF of demonstrating the existence of polymorphic drug oxidation.…”

“…However, this drug has two polymorphic pathways, namely a-hydroxylation (about 10% of the dose in EM) and O-dealkylation (about 60% of the dose in EM) (Lennard et al, 1982;McGourty et al, 1985). Thus, initial simulations were done using a single polymorphic pathway but with partial clearance down the polymorphic route set at the geometrical mean of the values for a-hydroxylation and O-dealkylation.…”