Jos Heykants

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan‐phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9‐hydroxyrisperidone, exhibited CYP2D6‐related polymorphism. The plasma area under the concentration—time curve from time zero to infinity ratio of 9‐hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half‐life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9‐hydroxyrisperidone) varied little among subjects (mean terminal half‐life, 20 ± 21/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients

The population pharmacokinetic parameters describing the plasma concentration versus time profile of alfentanil in patients undergoing general anesthesia were determined from 614 plasma concentration measurements collected in four previously reported studies with a total of 45 patients. A nonlinear regression analysis evaluating the effect of six concomitant variables revealed a significant influence of body weight on the volume of the central compartment (Vc), and a decrease with age of total body clearance (CL) and of redistribution rate from the deep compartment (k31). A small but significant effect of sex on the Vc was also observed. The duration of anesthesia and the concomitant administration of inhalational anesthetics had no effect on alfentanil pharmacokinetic parameters. The mean CL and Vc for alfentanil in a 70-kg male, aged less than 40 yr, were estimated as 0.356 l/min and 7.77 l, respectively. After correction for age, body weight, and sex, the remaining interindividual variability of alfentanil kinetics (expressed as coefficient of variation) was 48% for CL and 33% for Vc. These population pharmacokinetic parameter estimates should increase the accuracy of predicting concentration-time profiles for intravenous alfentanil infusions. A computer program is presented that allows prediction of the alfentanil plasma concentration and the 68% interval limits of the prediction from the study data analysis.

The Pharmacokinetics of Sufentanil in Surgical Patients

The pharmacokinetics of sufentanil, a new thienyl analogue of fentanyl, were studied in 10 surgical patients. Sufentanil, 5 μg/kg, was given intravenously as a bolus injection and plasma concentrations measured at intervals up to 8 h. Plasma sufentanil concentrations decreased rapidly after injection—98% of the administered dose having left the plasma within 30 min. In 9 of the 10 patients, a tri-exponential equation optimally described the sufentanil concentration decay curve, with average (±SEM) half-lives for the rapid (π) and slow (α) distribution phases of 1.4 ± 0.3 min and 17.7 ± 2.6 min, respectively. The average terminal elimination (β) half-life was 164 ± 22 min. The average value for Vdβ was 2.9 ± 0.2 1/kg, Vdss 1.7 ± 0.2 1/kg and total plasma clearance 12.7 ± 0.8 ml · kg-1 · min-1 (935 ± 50 ml/min). In one patient, a biexponential equation was sufficient to describe the concentration-time data, yielding a distribution half-life of 4.7 min and an elimination half-life of 117 min.

Linearity of Pharmacokinetics and Model Estimation of Sufentanil

Background The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed.

Pharmacokinetics of alfentanil in man.

The distribution and elimination kinetics of alfentanil, a new short-acting analgesic, were studied in five surgical patients. Its behavior, following a bolus injection of 120 μg/ml, was compatible with a three-compartment open-model distribution. The disappearance of the drug from plasma was rapid (t½π = 3.5 ± 1.3 minutes, t½α = 16.8 ± 6.4 minutes) with 96.4% of the drug eliminated from plasma in 1 hour, indicating extensive transfer to the remote peripheral compartment. This was followed by a slower elimination phase with a t½β of 94 ± 38 minutes. Total volume of distribution was 1.03 ± 0.50 L/kg. Total plasma clearance was 456 ± 155 ml/min. The short analgesic effect of this drug might be attributed to the rapid displacement of the drug from the central and intermediate compartments to the remote peripheral compartment. Approximately 25% of the injected dose was present in the remote peripheral compartment 30 to 60 minutes after alfentanil administration. As the return of drug from this peripheral to the central compartment is slower than the elimination rate of the drug, it could be the rate-limiting step in the elimination of alfentanil from the body.

Induction potential of antifungals containing an imidazole or triazole moiety: miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses

Male Wistar rats were dosed with miconazole, ketoconazole and itraconazole by gastric intubation once daily for up to 7 days. A dose- and time-dependent induction of the hepatic drug metabolizing enzyme system was observed for miconazole and ketoconazole, while itraconazole proved to be devoid of inductive properties even at the highest dose studied (160 mg/kg). No effect on drug metabolizing enzymes could be demonstrated for either drug at a dose level of 10 mg/kg, which is just above the antifungally active dose. At a dose of 40 mg/kg, miconazole, but not ketoconazole, significantly increased cytochrome P-450 content. At the highest dose of 160 mg/kg, both miconazole and ketoconazole increased the relative liver weight, the cytochrome P-450- and b5-content and NADPH-cyt c-reductase. Furthermore, miconazole, but not ketoconazole, increased specific microsomal aminopyrine and N,N-dimethylaniline N-demethylase activity, p-nitroanisole O-demethylase activity and UDP-glucuronyltransferase activity towards 4-nitrophenol while the specific aniline hydroxylase activity was unaffected. Ketoconazole at 160 mg/kg only induced O-demethylase activity and UDP-glucuronyltransferase activity, while it lowered the specific activities towards the other substrates. Miconazole was a relatively more potent inducer when compared to ketoconazole. Both drugs displayed biphasic effects on the mixed-function oxidase activities, which were lowered after acute administration (160 mg/kg, 1 hr before death) and were induced when determined after 23 hr had elapsed or after multiple dosage. Both drugs bound strongly to their respective induced cytochromes, giving rise to type II difference spectra, and inhibited the O-demethylase activity of the induced microsomes with an I50 of 5.2 microM for miconazole and 15.1 microM for ketoconazole. On the basis of a comparison of the enzymatic activities induced by both antimycotics with those induced by PB or 3-MC, it was concluded that miconazole behaved as a PB-type inducer, whereas ketoconazole did not belong to either category of inducers. A comparison of electrophoretograms of microsomes from different origins on SDS-PAGE revealed that miconazole increased the concentration of several proteins, whereas ketoconazole selectively induced a protein with Mr of 47,800. The protein pattern in the 50 kDa region of miconazole-induced microsomes resembled that of PB-microsomes qualitatively.

Alfentanil kinetics in the elderly.

Alfentanil disposition after an intravenous bolus of 50 µg/kg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two‐compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; X̄), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/min/kg) than in young adults (6.5 ml/min/kg), whereas terminal plasma t½ was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long‐term infusions are required.

Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography

A high-performance liquid chromatographic method has been developed for the simultaneous determination of the new antipsychotic risperidone and its major metabolite 9-hydroxyrisperidone in plasma, urine and animal tissues. The alkalinized plasma samples were extracted with ethyl acetate and further purified prior to reversed-phase chromatography with ultraviolet detection at 280 nm. The method could also be applied to urine samples and animal tissue homogenates. Quantification limits were 2 ng/ml for plasma and urine and 10 ng/g for animal tissue. The method was applied to pharmacokinetic studies in experimental animals, human volunteers and patients.

Clinical Pharmacokinetics of Ketanserin

SummaryKetanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite.Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40mg twice daily, steady-state concentrations fluctuate between 40 µg/L (trough) and 100 to 140 µg/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with β-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations.In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency. In elderly patients over 65 years of age the pharmacokinetics were similar to those found in healthy subjects; if anything, the bioavailability and area under the plasma concentration-time curve tended to be higher in some patients. In patients with severe hepatocellular insufficiency, the bioavailability of ketanserin is markedly higher due to a reduced hepatic elimination; in spite of higher plasma concentrations the terminal half-life is not changed. In view of these observations a higher dosage than 20mg twice daily is not likely to be required. In patients with renal insufficiency, elimination of the metabolite ketanserin-ol is prolonged but adaptation to lower doses of ketanserin is probably not necessary since plasma concentrations of the parent compound are similar to those seen in patients with normal kidney function.Studies in vitro with ketanserin at concentrations normally seen in patients on long term therapy indicate that ketanserin does not displace other drugs from their protein binding sites in plasma. Conversely, the protein binding of ketanserin is not influenced by the coadministration of other highly bound drugs. There is no evidence that ketanserin induces or reduces hepatic enzyme systems, and it is therefore unlikely that ketanserin treatment will have clinically important effects on the metabolism of concurrently administered drugs, but formal interaction studies are lacking. Combined treatment with propranolol or cimetidine did not influence the pharmacokinetics of ketanserin. Furthermore, ketanserin did not appreciably alter the single-dose pharmacokinetics of digoxin and digitoxin or the steady-state concentrations of digoxin during long term therapy.

Determination of levamisole in plasma and animal tissues by gas chromatography with thermionic specific detection.

A rapid and sensitive method has been developed for the determination of the anthelmintic levamisole in plasma and tissues from man and animals. The procedure involves the extraction of the drug and its internal standard from the biological material at alkaline pH, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane-isoamyl alcohol). Several extraction steps can be omitted, however, whenever the gas chromatographic background permits and some operations can be simplified using Clin ElutTM extraction tubes. The analyses were carried out by gas chromatography using a nitrogen-selective thermionic specific detector. The detection limit was 5 ng, contained in 1 ml of plasma or in 1 g of the various tissues, and recoveries were sufficiently high (79-86%). The method was applied to human plasma samples in a comprehensive bioavailability study of levamisole in healthy volunteers, and to plasma and tissues in a residue trial in cattle. The effect of the blood collection technique on the plasma levels was also studied and pointed to decreased plasma concentrations when Vacutainer tubes were used.