Urinary metabolites of timolol from humans and laboratory animals. Syntheses and .beta.-adrenergic blocking activities

Wasson, B. K.; Scheigetz, John; Rooney, C. S.; Hall, R. A.; Share, N. N.; Vandenheuvel, W.J.A.; Arison, Byron H.; Hensens, Otto D.; Ellsworth, Robert L.; Tocco, D J

doi:10.1021/jm00185a006

Cited by 16 publications

(7 citation statements)

References 3 publications

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“…Cleavage of the morpholino ring constitutes the major known pathway, the products of this reaction accounting for 40% of urinary recovery (Tocco et al 1975). It has been suggested that this cleavage reaction is the result of O-dealkylation subsequent to oxidative attack on the carbon atom adjacent to the morpholino ring oxygen atom (Wasson et al 1980). This pathway may well be under polymorphic control since a heterocyclic ring system is also the site of the 4-hydroxylation of debrisoquine.…”

Section: Metabolismmentioning

confidence: 98%

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Lennard

Tucker

Woods

1986

Clinical Pharmacokinetics

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Wide variability in response to some drugs such as debrisoquine can be attributed largely to genetic polymorphism of their oxidative metabolism. Most beta-blockers undergo extensive oxidation. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers (PMs) of debrisoquine have claimed that the oxidation of these drugs is under polymorphic control. Subsequently, 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, timolol and bopindolol. The poor metaboliser phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, viz. alpha-hydroxylation and O-demethylation of metoprolol and 1'- and possibly 4- and 6-hydroxylation of bufuralol. In contrast, the overall pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lower in poor metabolisers. As anticipated, the disposition of atenolol which is eliminated predominantly unchanged by the kidney and in the faeces, is unrelated to debrisoquine phenotype. The clinical significance of impaired elimination of beta-blockers is not clear. If standard doses of beta-blockers are used in poor metabolisers, these subjects may be susceptible to concentration-related adverse reactions and they may also require less frequent dosing for control of angina pectoris.

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Section: Metabolismmentioning

confidence: 98%

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Lennard

Tucker

Woods

1986

Clinical Pharmacokinetics

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“…Based upon earlier studies of the metabolism of other morpholine ring-containing molecules, Wasson et al (1980) subsequent to oxidative attack at one of the carbon atoms adjacent to the oxygen atom (Figure 1). Further oxidation would then lead to the formation of TG, which may then undergo decarboxylation and N-demethylation to produce TE.…”

Section: Discussionmentioning

confidence: 99%

Timolol metabolism and debrisoquine oxidation polymorphism: a population study.

Lennard

Lewis

Brawn

et al. 1989

Brit J Clinical Pharma

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1 The metabolism of orally administered timolol (T) to its ring cleavage ethanolamine (TE) and glycine (TG) products was studied in 108 unrelated hypertensive patients. 2 Statistically significant correlations between the 0-8 h urinary debrisoquine/4-hydroxydebrisoquine ratio and the T/TE (rs = 0.74, P < 0.001), T/TG (rs = 0.42, P < 0.001) and T/TE+TG (rs = 0.49, P < 0.001) ratios were found. 3 The log1o T/TE, T/TG and T/TE+TG ratios from poor metabolisers of debrisoquine (PMs) were grouped at the upper end of a unimodal distribution. 4 These results indicate that timolol metabolism is partly under monogenic control of the debrisoquine-type.5 The mean ± s.d. plasma timolol concentration in PMs (82 ± 43 ng ml-') was double that in extensive metabolisers (45 ± 19 ng ml-') (P = 0.011). The clinical significance of this observation remains to be established.

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“…There is no evidence that the metabolism of the isopropylamino side-chain of P-adrenoceptor antagonists is subject to polymorphic control of the debrisoquine type. One of the products of ring cleavage possesses weak P-adrenoceptor blocking activity in dogs (Wasson et al, 1980) …”

Section: Discussionmentioning

confidence: 99%

Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics.

Lewis¹,

Lennard²,

Jackson³

et al. 1985

Brit J Clinical Pharma

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1 The pharmacokinetics and pharmacodynamics of atenolol and timolol were studied in six extensive and four poor metabolisers of debrisoquine. 2 There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and the area under the plasma concentration time curve (AUC) for timolol (rs = 0.75, P < 0.02). The mean of the AUC values for timolol was significantly greater in the poor metabolisers than in the extensive metabolisers (P < 0.05). 3 There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and ,B-adrenoceptor blockade 24 h after dosing with timolol (rs = 0.66, P < 0.05). The mean degree of ,-adrenoceptor blockade was significantly greater in the poor metabolisers than in the extengive metabolisers 24 h after dosing with timolol (P < 0.01).4 There was no relation between the debrisoquine to 4-hydroxydebrisoquine ratio and the pharmacokinetics or pharmacodynamics of atenolol.

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Urinary metabolites of timolol from humans and laboratory animals. Syntheses and .beta.-adrenergic blocking activities

Cited by 16 publications

References 3 publications

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Timolol metabolism and debrisoquine oxidation polymorphism: a population study.

Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics.

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