Clinical pharmacology and therapeutics
-
Clin. Pharmacol. Ther. · Apr 2004
Comparative Study Clinical TrialChanges in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding.
Cardiopulmonary bypass is known to result in a reduction in the plasma binding of drugs. The resulting effect on the hepatic clearance of drugs with low extraction is well understood. However, the situation with those that are highly extracted is less clear. Studies were, therefore, undertaken with one such drug, propofol, for which plasma binding was changed during cardiac surgery with cardiopulmonary bypass. ⋯ During cardiopulmonary bypass, a significant increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood. The effect of the changes of propofol's protein binding on its kinetics was consistent with the predictions based on the well-stirred model of hepatic elimination for an intravenously infused high-clearance drug. Our finding on propofol pharmacokinetics may be the first example demonstrating the theoretic prediction of the well-stirred model.
-
Clin. Pharmacol. Ther. · Apr 2004
Clinical TrialSt John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism.
Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans. ⋯ Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.
-
Clin. Pharmacol. Ther. · Mar 2004
Comparative StudyCyclic antidepressants and the risk of sudden cardiac death.
Tricyclic and other related cyclic antidepressants (TCAs), used frequently for the treatment of depression and several other indications, have cardiovascular effects that may increase the risk of sudden cardiac death. We thus sought to quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs). ⋯ Our data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death.
-
Clin. Pharmacol. Ther. · Mar 2004
Randomized Controlled Trial Comparative Study Clinical TrialSt John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole.
St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. ⋯ St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.