Human pharmacokinetics and metabolism of disopyramide enantiomers.

The objective of the present study was to investigate human pharmacokinetics and metabolism of disopyramide (DP) enantiomers. Six healthy male volunteers entered the study. They were given, separately and via oral route, as repeated doses for 5 days, R(-) DP and S(+) DP at a dose of 100 mg twice daily. Unbound fractions of DP and metabolite (MND) enantiomers were obtained on each plasma sample, i.e. ex vivo, using ultrafiltration. Pharmacokinetic parameters of DP enantiomers based on total plasma concentrations were not significantly different. On the other hand, unbound pharmacokinetic parameters displayed marked stereoselectivity. The mean unbound clearance of R(-) DP and S(+) DP were 8.59 and 14.9 ml/min/kg, respectively (p = 0.003). The mean unbound renal clearance of R(-) DP and S(+) DP were 6.26 and 8.75 ml/min/kg, respectively (p = 0.025). The non renal clearance of R(-) DP and S(+) DP averaged 2.32 and 6.19 ml/min/kg, respectively (p = 0.002). The mean unbound volume of distribution of R(-) and S(+) DP were 225 and 381 liters, respectively (p = 0.023). The half-life of R(-) DP and S(+) DP averaged 4.17 and 3.91 hr, respectively (p = 0.21). The unbound fraction at steady-state of R(-) DP and S(+) DP averaged 12.5 and 7.5%, respectively (p = 0.002). In vitro binding experiments, performed for each subject, allowed to indicate that the stereoselective plasma binding was due to a stereoselective affinity, the binding capacity of both enantiomers being the same. Pharmacokinetic data emphasized the influence of stereoselectivity in the human disposition of DP enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro assessment of stereoselective hepatic metabolism of disopyramide in humans: comparison with in vivo data.

Metabolism of disopyramide (DP) enantiomers has been investigated in primary cultures of adult human hepatocytes. Results were compared with in vivo data obtained from a previous pharmacokinetic study (Le Corre et al. Drug Metab. Dispos. 16:858-864 1988). Metabolism of DP enantiomers as a function of incubation time showed constant velocity over time. The intracellular/extracellular distribution of both DP and mono-N-desisopropyldisopyramide did not appear to be stereoselective. Metabolism of DP enantiomers as a function of substrate concentration followed a first order kinetics. The average fractions of (-)-(R)-DP and (+)-(S)-DP metabolized in vitro (4.7 +/- 2.7 and 7.1 +/- 4.2%, respectively, n = 4) were about 5-fold lower than the fractions metabolized in vivo (26.0 +/- 6.0 and 40.2 +/- 8.8%, respectively, n = 6). The stereoselective index [(+)-(S)/(-)-(R)] of the N-dealkylation pathway obtained in vitro (1.51 +/- 0.11, n = 4) was very close to the one obtained in vivo (1.55 +/- 0.10, n = 6). These results highlight the interest of hepatocyte cultures in the evaluation of drug metabolism and especially in the assessment of stereoselectivity.

Clinical pharmacokinetics of levorotatory and racemic disopyramide, at steady state, following oral administration in patients with ventricular arrhythmias.

Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(-) DP) and racemic disopyramide (equimolar mixture of R(-) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind cross-over randomized trial was achieved, at steady-state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(-) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P less than .01), and QTc interval (+9.2% and +7%, respectively, P less than .001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(-) DP (157 ml/min), (P less than .001). The mean total plasma clearance of R(-) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(-) DP, due to the presence of S(+) DP, which is known to be a potent displacer of R(-) DP.

[The effect of modification of excipients for the bioavailability of vinburnine]. / Influence d'une modification d'excipients sur la biodisponibilité de la vinburnine.

Biopharmaceutic comparison is achieved between commercialized capsules of vinburnine and a new dosage form. The difference between the two drug products concerns only the quality of excipients. Drug bioavailability decreases of about 10%, in despite of the very important, and well known, interindividual variations of vincamine drug products. Only the absorption rate seems statistically lightly decreased by the new formulation.

[The oral liquid form of vinburnine: biopharmaceutics]. / Forme buvable de vinburnine: une approche biopharmaceutique.

Biopharmaceutic comparison is achieved between commercialized capsules of vinburnine and drops dosage form intended for geriatric pharmacotherapy. Drug bioavailability of vinburnine seems saved, if not significantly increased by the new formulation, in spite of the very important, and well known interindividual variations of vincamine drug products. Only the absorption rate seems statistically increased by drops.

[Simultaneous determination of vinburnine and 6-hydroxyvinburnine in human plasma by high-performance liquid chromatography]. / Dosage simultané de la vinburnine et de la 6-hydroxyvinburnine par chromatographie liquide à haute performance.

An isocratic high-performance liquid chromatographic method has been developed to allow the simple and rapid determination of both vinburnine (I) and its main metabolite, 6-hydroxyvinburnine (II), in heparinized human plasma (0.5 ml). Compounds I and II and p-chlorodisopyramide (internal standard) were first extracted with alkalinized ethyl acetate and then with sulphuric acid. Separation was achieved on a reversed-phase muBondapak C18 column with a mobile phase of acetonitrile-water-0.1 M heptanesulphonate in acetic acid and with detection at 254 nm. Each run required 20 min. The within-day coefficients of variation for identical samples (20 ng/ml) were 7 and 6% and between-day coefficients of variation 8 and 26% for I and II, respectively. The detection limit was 5 ng/ml (normal therapeutic concentration, 10-300 ng/ml). The application of the method to drug monitoring was compared to that of a thin-layer chromatographic procedure.

Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans.

Metabolism, pharmacokinetics, and influence of alpha 1-acid glycoprotein (alpha 1-AGP) plasma levels on protein binding of (R)-(-) and (S)-(+)-disopyramide (DP) were compared, in six healthy subjects, at the steady state, after oral administration of 100 mg twice daily. The mean unbound clearance of (R)-(-)-DP and (S)-(+)-DP were 8.59 and 14.9 ml/min/kg, respectively (p = 0.003). The mean unbound renal clearance of (R)-(-)-DP and (S)-(+)-DP were 6.26 and 8.75 ml/min/kg, respectively (p = 0.025). The nonrenal clearance, i.e. hepatic metabolic clearance, of (R)-(-)-DP and (S)-(+)-DP averaged 2.32 and 6.19 ml/min/kg, respectively (p = 0.002). The mean unbound volume of distribution of (R)-(-)- and (S)-(+)-DP were 225 and 381 liters, respectively (p = 0.023). The half-life of (R)-(-)-DP and (S)-(+)-DP averaged 4.17 and 3.91 hr, respectively (p = 0.21). The mean unbound renal clearance of (R)-(-)- and (S)-(+)-mono-N-dealkylated disopyramide (MND) were 3.21 and 7.02 ml/min/kg, respectively (p less than 0.001). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-DP averaged 12.5 and 7.5%, respectively (p = 0.002). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-MND averaged 62.6 and 60.5%, respectively (p = 0.36). The highest alpha 1-AGP plasma concentration resulted in lower unbound fraction for both DP and MND enantiomers, whereas the lowest alpha 1-AGP plasma concentration resulted in higher unbound fraction for (S)-(+)-DP only.

Direct enantiomeric resolution of disopyramide and its metabolite using chiral high-performance liquid chromatography. Application to stereoselective metabolism and pharmacokinetics of racemic disopyramide in man.

A method for the simultaneous determination of disopyramide and mono-N-desisopropyldisopyramide enantiomers extracted from human plasma and urine is presented. Separation and quantitation were carried out using two columns coupled in series, and UV detection at 254 nm. First, the racemates of the two compounds were separated using a reversed-phase column, and then the enantiomers were separated using a stereoselective column packed with human alpha 1-acid glycoprotein. The mobile phase was 8 mM phosphate buffer, pH 6.20-2-propanol (92:8, v/v). The coefficients of variation (%) for the plasma daily determination were 6.7% for R(-)- and S(+)-disopyramide at drug levels of 1.5 micrograms/ml, and 8.5% and 7.7% for R(-)- and S(+)-mono-N-desisopropyldisopyramide, respectively, at drug levels of 0.375 micrograms/ml. The method has allowed the study of stereoselective metabolism and pharmacokinetics of disopyramide after oral administration as a racemate.

[Prolonged intravenous infusion of morphine. Pharmacokinetic study]. / Perfusion intraveineuse prolongée de morphine. Etude pharmacocinétique.

Critically ill patients require optimal pain control without undesirable side-effects. Continuous intravenous morphine infusion is often chosen instead of the conventional intermittent administration. In the present study, the pharmacokinetic characteristics of morphine were studied in five subjects receiving a constant rate intravenous infusion with the attainment of a steady state. The plasma levels were compared with values derived from bolus intravenous administration in five other patients. The concentrations of unchanged morphine were determined in serum using high performance liquid chromatography with an electrochemical detector. The decay of plasma concentrations after a single dose fitted a triexponential function consistent with a three compartment pharmacokinetic model. Postinfusion plasma concentrations fitted a two compartment model. Derived values (mean +/- SEM) of total body clearance were significantly different between groups (p less than 0.05), while mean values of terminal elimination half-life (t 1/2 Kel) were similar. It was concluded that values of total distribution volume were significantly different. The extent of morphine distribution varied more than twofold between the two groups of patients. This was interpreted as a consequence of an important underestimation in the extent of distribution tissues after administration of a single dose.