Polymorphic Hydroxylation of Debrisoquine

Tucker, GT; Silas, J H; Iyun, AO; Lennard, M. S.; Smith, Anthony

doi:10.1016/s0140-6736(77)90527-x

Cited by 102 publications

(47 citation statements)

References 4 publications

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“…The ratio of debrisoquine/4-hydroxydebrisoquine (D/ HD) in poor metabolisers is >20; that in extensive metabolisers is <12 (mode <1) (Mahgoub et al, 1977;Tucker et al, 1977).…”

Section: Oxidation Statusmentioning

confidence: 99%

Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

Freestone¹,

Silas²,

Lennard³

et al. 1982

Brit J Clinical Pharma

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1 Eight healthy men received two long-acting formulations of metoprolol 200 mg (SA Astra, SR Geigy), conventional metoprolol 200 mg and atenolol 100 mg once daily for 1 week each in balanced, crossover fashion. There was a washout period of at least a week between each phase. 2 On the last day of each phase, post-exercise heart rate was recorded at intervals and compared to pretreatment values. Plasma metoprolol concentrations were measured. 3 The mean AUC was similar after each of the three formulations of metoprolol (relative bioavailability of SA and SR v conventional was 97%) but with SA and SR metoprolol the time to peak was significantly delayed by about 2 h. 4 In comparison to conventional metoprolol only metoprolol SA was associated with significantly higher plasma metoprolol concentrations at the end of a dosing interval (mean values: conventional, 25 ng/ml, SR 37 ng/ml, SA 51 ng/ml). 5 Mean (+ s.d.) reduction in exercise tachycardia at the end of a dosing interval was significantly greater with atenolol (14.8 + 4.5%) and metoprolol SA (13.7 + 10.3%) than with metoprolol SR (10 + 8.4%) and conventional metoprolol (8.2 + 7.1%). 6 The variability in /3-adrenoceptor blockade at 24 h was much greater with each of the three metoprolol formulations than that with atenolol. This was explained by the variability in metoprolol metabolism. 7 Oxidation phenotype testing with debrisoquine showed there were six extensive metabolisers and two poor metabolisers. The AUC, half-life and response to metoprolol at 24 h were much greater in poor metabolisers. Response to atenolol was not influenced by phenotype.

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“…The ratio of debrisoquine/4-hydroxydebrisoquine (D/ HD) in poor metabolisers is >20; that in extensive metabolisers is <12 (mode <1) (Mahgoub et al, 1977;Tucker et al, 1977).…”

Section: Oxidation Statusmentioning

confidence: 99%

Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

Freestone¹,

Silas²,

Lennard³

et al. 1982

Brit J Clinical Pharma

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“…Classification of individuals as extensive metabolisers (EM) or poor metabolisers (PM) is conveniently achieved by measurement of the debrisoquine/4-hydroxydebrisoquine ratio in urine following a single oral dose of 10 mg debrisoquine (Mahgoub et al, 1977). The polymorphism has been shown to extend in vivo to the oxidative metabolism of sparteine (Inaba, Otton & Kalow, 1980;Bertilsson, Dengler, Eichelbaum & Schulz, 1980), phenacetin (Sloan, Mahgoub, Lancaster, Idle & Smith, 1978) and several other drugs (Ritchie, Sloan, Idle & Smith, 1980), though not to a number of drugs such as antipyrine (Tucker, Silas, Iyun, Lennard & Smith, 1977;Inaba etal., 1980). The present study was undertaken to establish whether the deficiency in the 4-hydroxylation of debrisoquine was due to relative lack of enzyme activity in the liver.…”

Section: Evidence For An Enzymatic Defect In the 4-hydroxylation Of Dmentioning

confidence: 99%

Evidence for an enzymatic defect in the 4‐hydroxylation of debrisoquine by human liver.

Davies¹,

Kahn²,

Murray³

et al. 1981

Brit J Clinical Pharma

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“…impaired ability to eliminate the drug by alicyclic A panel study has indicated that the metabolism hydroxylation, the major route of metabolism of metoprolol cosegregates with that of debriso- (Mahgoub et al, 1977;Tucker et al, 1977; Evans quine. Thus, PMs had higher plasma metoprolol et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

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

McGourty¹,

Silas²,

Lennard³

et al. 1985

Brit J Clinical Pharma

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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.

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Polymorphic Hydroxylation of Debrisoquine

Cited by 102 publications

References 4 publications

Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

Evidence for an enzymatic defect in the 4‐hydroxylation of debrisoquine by human liver.

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

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