S. Toon

Enoxacin‐warfarin interaction: Pharmacokinetic and stereochemical aspects

The interaction between the new quinoline‐azaquinoline antibiotic enoxacin and the oral anticoagulant warfarin was investigated in six healthy male volunteers. Enoxacin was found not to affect the hypoprothrombinemic response produced by warfarin but did produce a decrease in the clearance of the less pharmacologically potent enantiomer of warfarin, (R)‐warfarin. The decreased clearance of (R)‐warfarin produced by concomitant enoxacin administration was found to be a consequence of inhibition by enoxacin of the (R)‐6‐hydroxywarfarin metabolic pathway.

Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man

SummaryStereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.

Validation of assay methodology used in pharmacokinetic studies

Statistical methods for validating assays used in pharmacokinetic studies are discussed. Methods for assessing linearity, variability, and sensitivity are derived. It is proposed that a calibration experiment, in which samples are replicated at three different concentrations, will provide the necessary information to validate an assay prior to commencement of a pharmacokinetic study and during its routine use. A two-stage weighted least squares regression is used to analyze the calibration data. High performance liquid chromatography calibration data are used to illustrate the principles and techniques involved.

The racemic metoprolol H2-antagonist interaction.

The effects of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of multiple‐dose metoprolol were investigated in 12 normal, healthy male volunteers. The pharmacokinetics of metoprolol were assessed in terms of racemic metoprolol and the individual (R)– and (S)–enantiomers with a stereoselective assay. Ranitidine had no effect on the pharmacodynamics or pharmacokinetics of metoprolol. Although not affecting the pharmacodynamics of metoprolol, cimetidine did produce an increase in the bioavailability of metoprolol through inhibition of enzymes responsible for the first‐pass elimination of the β‐blocker. The effect was stereoselective, with the major effect being on the less pharmacologically active (R)–enantiomer.

Rate and Extent of Absorption of Clonidine from a Transdermal Therapeutic System

Abstract— The in‐vivo performance of a clonidine transdermal therapeutic system (TTS 3·5 cm2, 2·5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4·32 μg h−1 over a 7‐day period.

The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans

AbstractObjective: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. Methods: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8–14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. Results: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (±SD) of R-6-hydroxywarfarin (31.1 ± 7.4 ml/h baseline; 18.5 ± 4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9 ± 1.3 ml/h baseline; 4.3 ± 1.1 ml/h at end of cimetidine treatment; P < 0.01). Conclusion: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients.

Absence of effect of ranitidine on blood alcohol concentrations when taken morning, midday, or evening with or without food

To investigate the effects of multiple dosing with ranitidine (300 mg four times a day) on the absorption of a moderate dose of alcohol (0.5 gm · kg−1), consumed postprandially or on an empty stomach at different times of day, and to investigate if coadministration of ranitidine affects psychomotor function.

The effect of renal function on the pharmacokinetics of ranitidine

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied.Renal function was assessed in each patient by 51Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC.Patient groups with renal impairment had significantly increased AUC∞ and t1/2 with corresponding decreases in CLp and λz when compared with normal subjects. There was also a significant increase in tmax but not in Cmax. There was a high linear correlation between the degree of renal impairment and ranitidine clearance.In patients with GFR ≤ 20 ml min−1, the AUC∞ mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min−1, the average AUC∞ ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR ≤ 20 ml min−1.

Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on “alertness” and “happiness”

A simple restraining device for chronic pharmacokinetic and metabolism studies in rats

The construction of a simple Plexiglas restraining device for chronically cannulated rats is described. The apparatus is ideally suited for blood sampling and the collection of urine and feces during chronic pharmacokinetic and drug metabolism studies.