J.P. Le Moing

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.

AbstractObjective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss · kg–1) 11.2 l ·  kg–1; total clearance (CL) 51.6 h–1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l · h–1) were significantly higher in obese patients. But Vss · kg–1 (9.4 l · kg–1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h–1) and the t1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography with electrochemical detection

A method for the determination of risperidone and its active metabolite 9-hydroxyrisperidone in human plasma has been developed. The procedure involved a multi-step liquid-liquid extraction with an internal standard. The parent drug and its metabolite were separated on a cyano column used in the reversed-phase model. The coulometric detection allows quantification in the range 2-100 ng/ml. The precision, accuracy and specificity have been checked, and show that the method is reliable for clinical studies.

COMPARATIVE PHARMACOKINETIC STUDY OF FENTANYL AND SUFENTANIL AFTER SINGLE HIGH-BOLUS DOSES

AbstractObjective: To investigate and compare the pharmacokinetic parameters of sufentanil and fentanyl during a prolonged period after single bolus administration, and to detect and compare the occurrence of secondary peaks of opioid plasma concentration. Design: This was a prospective, double-blind, randomised study in surgical patients. Patients: Forty-one patients, aged ≥35 years, undergoing coronary artery bypass graft surgery, were randomised to anaesthesia with sufentanil/O2 (n = 20) or fentanyl/O2 (n = 21). Methods: Arterial blood samples were taken up to 24 hours after administration for determination of plasma opioid concentrations, and haemodynamic parameters were monitored during and after the surgical procedure. Pharmacokinetic data were analysed by compartmental analysis and by population analysis using a nonlinear mixed-effect modelling approach. Results: There were no significant differences in demographics, features of the surgical procedure or haemodynamic parameters between the two groups. By population analysis, the terminal elimination half-life (t1/2z) of fentanyl was 20.7 hours, total body clearance (CL) was 4.7 ml/min/kg and volume of distribution at steady state (Vss) was 5.2L/kg. For sufentanil, t1/2z was 37.7 hours, CL was 7.4 ml/min/kg and Vss was 13.9 L/kg. No correlation was observed between demographic data and pharmacokinetic parameters for sufentanil, whereas for fentanyl significant correlations were revealed between age and Vss, t1/2z and the intercompartmental transfer rate constant k21. Significant differences were observed in the occurrence of secondary peaks, which occurred in nine patients receiving fentanyl (with two patients exhibiting double secondary peaks) and in one patient receiving sufentanil (p = 0.02). Conclusions: Our study allowed a better determination of the pharmacokinetic parameters of high-dose sufentanil administered as a single bolus, and we demonstrated a clear pharmacokinetic difference between fentanyl and sufentanil in terms of higher CL and larger Vss for sufentanil. These pharmacokinetic differences have not had clinically relevant consequences in our study. However, the occurrence of secondary peaks, which have been considered as a risk factor in the postoperative period, is significantly reduced with sufentanil compared with fentanyl.

Comparaison de la pharmacocinétique de l'étomidate chez l'enfant et chez l'adulte

Etomidate pharmacokinetics were compared in 12 children (P group) (age 7 to 13 years, weight 22 to 48 kg) and in 4 adult women (A group) (age 28 to 52 years, weight 46 to 72 kg), A.S.A. 1, undergoing minor non abdominal surgery. They were unpremedicated and anaesthetized with alfentanil 100 μg · kg−1 and isoflurane 2 vol % in N2O/O2 (1/1). Etomidate was administered as a bolus : 0.3 mg · kg−1 in adults and 0.4 mg · kg−1 in children. Venous plasma samples were frozen until further etomidate assay with a HPLC technique. In all patients but two children, data were fitted to a three rather than a two compartment model. Differences between groups (mean ± SD values) included Vdc (P : 0.66 ± 0.31 l · kg−1 ; A : 0.27 ± 0.15 l · kg−1 ; p < 0.01), t1/2π (P : 5.4 ± 2.9 min ; A : 2.7 ± 5.7 min ; p < 0.05) and plasma clearance (P : 17.2 ± 4.6 ml · kg−1 · min−1 ; A : 10.9 ± 3.3 ml · kg−1 · min−1 ; p < 0.05). No statistical difference was found between A and P groups for the following parameters : t1/2 α (37.1 ± 12.0 min vs 26.8 + 15.1 min), t1/2 β (260 ± 99 min vs 175 ± 99 min), Vdss (2.5 ± 1.1 l · kg−1 vs 2.8 ± 1.6 l · kg−1), Vdβ (4.1 ± 2.4 l · kg−1 vs 4.0 ± 2.2 l · kg−1), and MRT (228 ± 80 min vs 172 ± 101 min). No age-related difference was found inside P group with regard to pharmacokinetic parameters. In conclusion, a 30 % higher etomidate bolus dosage is required in children than in adults to achieve similar plasma concentrations, due to a higher volume of the initial compartment. In comparison to adults the higher clearance suggests higher maintenance dose requirements in children.

Reversed-phase high-performance liquid chromatographic separation of 14C-labelled toloxatone and its metabolites.

A method for the analytical and micropreparative separation of toloxatone and its urinary metabolites in man is described. Toloxatone was given as an aqueous solution and was labelled with 14C. Following solvent extraction of urine, before and after enzymatic hydrolysis, one-step thin-layer chromatography on silica gel in combination with reversed-phase high-performance liquid chromatography, gave a good micropreparative separation for mass spectrometric analysis. After lyophilization of the high-performance liquid chromatographic fractions, the purity of the metabolites was checked by thin-layer chromatography. Acetic acid was chosen to regulate the pH of the mobile phase (acetonitrile-water) because it can be easily removed by lyophilization when a preparative separation is desired. The retention times as a function of the pH have been evaluated. Formic acid is also proposed for the optimization of the high-performance liquid chromatographic analysis. The quantitative analysis of 14C-labelled toloxatone and its metabolites was carried out, after solvent extraction of 2 ml of urine, using the same high-performance liquid chromatographic method with off-line and flow-through radioactivity detection.

Gas—liquid chromatographic determination of toloxatone in human plasma : Routine analysis of a wide range of drug concentrations using a nitrogen-selective detector

A selective and sensitive gas--liquid chromatographic (GLC) method has been developed for the measurement of toloxatone at therapeutic concentrations in plasma. The technique is based on a single extraction from plasma at pH 10, the preparation of a trimethylsilyl derivative and detection by a nitrogen-selective detector. The traditional calibration curve, peak-area ratio of toloxatone to internal standard versus toloxatone plasma concentration, was slightly concave for the wide concentration considered (10-3000 ng/ml). As a consequence, the linear least-squares regression analysis gave a negative intercept on the gamma-axis which affected quantitation accuracy of low plasma concentration values. A calibration method taking into consideration the non-linearity of the calibration curve is proposed. The characteristics of the detector were examined in order to analyse response linearity and sensitivity. A linear relationship was found between background current and detector sensitivity.

Determination of low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol using gas chromatography—negative-ion chemical ionization mass spectrometry

Gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) allowed the detection of extremely low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Glucuronide and sulphate conjugates of MHPG were determined after enzymatic hydrolysis of plasma with beta-glucuronidase-arylsulphatase. A 1-ml plasma sample was extracted at the pH of the hydrolysis (pH 4.8) with ethyl acetate, and the dry extract was derivatized with pentafluoropropionic anhydride in ethyl acetate. After evaporation of the solvent, the residue was dissolved in benzene and an aliquot was analysed by GC-NICI-MS. A trideuterated analogue of MHPG was used as an internal standard. Negative-ion chemical ionization of the pentafluoropropionyl derivatives was carried out using ammonia. The ion-molecule adducts at m/e 766 and 785 (MHPG) and m/e 769 and 788 (internal standard) were formed from the pentafluoropropionyl derivatives with the ions of m/e 163 (CF3CF2COO-) and m/e 144 (loss of fluorine from m/e 163). The concentrations of the ions of m/e 163 and 144 play a major role in the sensitivity and precision of this technique, which allows the detection of free MHPG plasma concentrations as low as 100 pg/ml in routine analysis.