HIGH PLASMA CONCENTRATIONS OF Β-Receptor BLOCKING DRUGS AND DEFICIENT DEBRISOQUINE HYDROXYLATION

Alván, Gunnar; Bahr, Christer von; Seideman, P; Sjöqvist, Folke

doi:10.1016/s0140-6736(82)91583-5

Cited by 81 publications

(23 citation statements)

References 10 publications

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“…The AUC of orally administered timolol has been 2-4 times larger in CYP2D6 PM subjects compared with EMs (Alvan et al, 1982;Lewis et al, 1985;McGourty et al, 1985). In the present study, the only PM subject had an exposure to paroxetine about 5 times higher than the average exposure to paroxetine, and the subject's systemic timolol exposure during the placebo phase was about 2-fold, compared with that in EMs.…”

Section: Cyp2d6 Inhibition Raises Ophthalmic Timolol Concentrations 2073contrasting

confidence: 47%

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

et al. 2014

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Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26-to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.

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Section: Cyp2d6 Inhibition Raises Ophthalmic Timolol Concentrations 2073contrasting

confidence: 47%

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

et al. 2014

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“…A genetic defect in the hydroxylation capacity in man has been described for debrisoquine (Mahgoub et al, 1977), and has been implicated recently in the poor ability of some individuals to metabolize a number of Padrenoceptor antagonists, including alprenolol, timolol (Alvan et al, 1982) and metoprolol (Lennard et al, 1982). Debrisoquine hydroxylation status was not determined in this study.…”

Section: Oxprenolol Assaymentioning

confidence: 79%

Oxprenolol absorption in man after single bolus dosing into two segments of the colon compared with that after oral dosing.

Antonin¹,

Bieck²,

Scheurlen³

et al. 1985

Brit J Clinical Pharma

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1 The systemic availability of oxprenolol after colonic and oral administration has been compared in a crossover study involving six healthy male volunteers. Drug administration into two regions of the colon (caecum and left flexure) was achieved by means of a colonoscopic technique. 2 There were no obvious differences in plasma concentrations after drug administration to the caecum and left flexure, although in one subject it was necessary to repeat colonic administration because of unexpectedly high plasma drug levels on the first occasion. The possible reasons for this abnormal response are discussed. 3 The mean systemic availability of oxprenolol was 82% after colonic compared with oral dosing, although marked differences were observed in individual plasma levels following drug administration by the two routes. 4 The results of this study support the concept of extending the duration of oxprenolol release from a rate-controlled dosage form to permit once-daily administration with this short elimination half-life drug.

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“…Since completing this work it has been suggested that a similar defect may also involve the metabolism of alprenolol and timolol (Alvan et al, 1982).…”

Section: Introductionmentioning

confidence: 92%

Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.

Lennard¹,

Silas²,

Freestone³

et al. 1982

Brit J Clinical Pharma

111

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Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of B-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and ,3-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.

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HIGH PLASMA CONCENTRATIONS OF Β-Receptor BLOCKING DRUGS AND DEFICIENT DEBRISOQUINE HYDROXYLATION

Cited by 81 publications

References 10 publications

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

Oxprenolol absorption in man after single bolus dosing into two segments of the colon compared with that after oral dosing.

Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.

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