Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole.

STUDY OBJECTIVE: To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-beta-cyclodextrin under fasting versus postprandial conditions. DESIGN: Open-label, two-way, randomized, crossover study. SETTING: Janssen Research Foundation, Belgium. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. MEASUREMENTS AND MAIN RESULTS: The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0-infinity and AUC0-24 hrs) were also significantly higher under fasting than under postprandial conditions. CONCLUSIONS: Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.

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. METHODS: The pharmacokinetics of sufentanil were investigated in 23 patients, aged 14-68 yr, scheduled for surgery with postoperative ventilation. After induction of anesthesia, sufentanil was administered as a short infusion (10-20 min) in doses ranging from 250 micrograms to 1,500 micrograms. Frequent arterial blood samples were gathered during and at the end of infusion, then at specific intervals up to 48 h after infusion. Plasma concentrations of sufentanil were measured by radioimmunoassay (limit of sensitivity 0.02 ng.ml-1). The data were analyzed with the standard two-stage, naive pooled-data and the mixed effect pharmacokinetic approaches. RESULTS: The pharmacokinetics of sufentanil were adequately described by a linear three-compartmental mamillary model with the following parameters, expressed as log mean values with 95% confidence intervals: the central volume of distribution = 14.3 l (13.1-15.41), the rapidly equilibrating volume = 63.1 l (61.9-64.3 l), the slowly equilibrating volume = 261.6 l (260.2-262.9 l), the steady-state distribution volume = 339 l (335-343 l), metabolic clearance = 0.92 l.min-1 (0.84-1.05 l.min-1), rapid distribution clearance = 1.55 l.min-1 (1.34-2.14 l.min-1), slow distribution clearance = 0.33 l.min-1 (0.27-0.49 l.min-1), and elimination half-life = 769 min (690-1011 min). No relation to age, weight, or lean body mass was found for any of the parameters. CONCLUSIONS: Sufentanil pharmacokinetics were linear within the dose range studied. Drug detection up to 24 h after dosing was necessary to define the terminal elimination phase. The metabolic clearance approached liver blood flow and a large volume of distribution was identified, consistent with the long terminal elimination half-life. Simulations predicted that plasma sufentanil steady-state concentrations would rapidly decline after termination of an infusion despite the long half-lives.

Gastrointestinal distribution of the prodrug loperamide oxide and its active drug loperamide in the dog.

Loperamide oxide is a prodrug of the effective antidiarrheal loperamide. Administration of this prodrug improves efficacy and tolerability. For better understanding of these effects, the absorption and gastrointestinal distribution of loperamide oxide and of its active drug loperamide were studied. Beagle dogs received a single oral dose of loperamide oxide or loperamide at 0.16 mg/kg. Plasma, gastrointestinal contents and tissues, and some other organs were obtained. Concentrations were determined by specific radioimmunoassays. Loperamide oxide was gradually converted to loperamide in the gastrointestinal tract. After administration of the prodrug, the systemic absorption of the active drug was lower and more delayed than after administration of loperamide itself. As a consequence, more loperamide was available in the contents and the mucosa of the gut, in particular in the lower part of the small intestine and in the large intestine. The higher levels of loperamide in mucosa may cause more pronounced and longer lasting antisecretory effects after administration of loperamide oxide. The results of this study are in line with the hypothesis that loperamide oxide is a site-specific prodrug that acts as a chemically designed controlled-release form of loperamide keeping a higher amount of the active drug for a longer time at the site of action in the gut wall.

Assay methods for sufentanil in plasma. Radioimmunoassay versus gas chromatography-mass spectrometry.

BACKGROUND: The terminal pharmacokinetic parameters of sufentanil have, until now, been poorly characterized. This is probably because of the poor sensitivity or unreliability of the assay methods used. Radioimmunoassay (RIA) can be a very helpful assay method for sufentanil. However, before application to key pharmacokinetic studies, it requires adequate validation, e.g., by comparison with a method of proven sensitivity and specificity, such as gas chromatography-mass spectrometry (GC-MS). METHODS: Spiked control plasma samples and 135 plasma samples obtained from five patients receiving intravenous doses of 500 or 750 micrograms sufentanil, as a 10-20-min infusion, were analyzed by an improved, sensitive RIA and capillary GC-MS. RESULTS: Both techniques had comparable limits of quantitation (0.02 ng/ml). Between-day coefficients of variation in the 0.05-10-ng/ml concentration range were 8.5-10.5% for the RIA and less than 10% for the GC-MS method. The patient plasma concentrations determined by RIA (y) and GC-MS (x) showed a good agreement (y = 1.016x + 0.002) and a correlation coefficient of 0.97. CONCLUSIONS: The results demonstrate the validity of the improved RIA method for the determination of sufentanil plasma concentrations.

Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.

Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action. The absorption, plasma levels and regional brain distribution of risperidone, metabolically formed 9-hydroxy-risperidone and total radioactivity were studied in the male Wistar rat after single subcutaneous administration of radiolabelled risperidone at 0.02 mg/kg. Concentrations were determined by HPLC separation, and off-line determination of the radioactivity with liquid scintillation counting. Risperidone was well absorbed. Maximum plasma concentrations were reached at 0.5-1 h after subcutaneous administration. Plasma concentrations of 9-hydroxy-risperidone were higher than those of risperidone from 2h after dosing. In plasma, the apparent elimination half-life of risperidone was 1.0 h, and mean residence times were 1.5 h for risperidone and 2.5 h for its 9-hydroxy metabolite. Plasma levels of the radioactivity increased dose proportionally between 0.02 and 1.3 mg/kg. Risperidone was rapidly distributed to brain tissues. The elimination of the radioactivity from the frontal cortex and striatum--brain regions with high concentrations of 5-HT2 or dopamine-D2 receptors--became more gradual with decreasing dose levels. After a subcutaneous dose of 0.02 mg/kg, the ED50 for central 5-HT2 antagonism in male rats, half-lives in frontal cortex and striatum were 3-4 h for risperidone, whereas mean residence times were 4-6 h for risperidone and about 12 h for 9-hydroxy-risperidone. These half-lives and mean residence times were 3-5 times longer than in plasma and in cerebellum, a region with very low concentrations of 5-HT2 and D2 receptors. Frontal cortex and striatum to plasma concentration ratios increased during the experiment. The distribution of 9-hydroxy-risperidone to the different brain regions, including frontal cortex and striatum, was more limited than that of risperidone itself. This indicated that 9-hydroxy-risperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted from plasma levels. AUCs of both active compounds in frontal cortex and striatum were 10-18 times higher than those in cerebellum. No retention of metabolites other than 9-hydroxy-risperidone was observed in any of the brain regions investigated.

A predictive model for substrates of cytochrome P450-debrisoquine (2D6).

Molecular modeling techniques were used to derive a predictive model for substrates of cytochrome P450 2D6, an isozyme known to metabolize only compounds with one or more basic nitrogen atoms. Sixteen substrates, accounting for 23 metabolic reactions, with a distance of either 5 A ("5-A substrates", e.g., debrisoquine) or 7 A ("7-A substrates", e.g., dextromethorphan) between oxidation site and basic nitrogen atom were fitted into one model by postulating an interaction of the basic nitrogen atom with a negatively charged carboxylate group on the protein. This acidic residue anchors and neutralizes the positively charged basic nitrogen atom of the substrates. In case of "5-A substrates" this interaction probably occurs with the carboxylic oxygen atom nearest to the oxidation site, whereas in the case of "7-A substrates" this interaction takes place at the other oxygen atom. Furthermore, all substrates exhibit a coplanar conformation near the oxidation site and have negative molecular electrostatic potentials (MEPs) in a part of this planar domain approximately 3 A away from the oxidation site. No common features were found in the neighbourhood of the basic nitrogen atom of the substrates studied so that this region of the active site can accommodate a variety of N-substituents. Therefore, the substrate specificity of P450 2D6 most likely is determined by the distance between oxidation site and basic nitrogen atom, by steric constraints near the oxidation site, and by the degree of complementarity between the MEPs of substrate and protein in the planar region adjacent to the oxidation site.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction potential of fluconazole toward drug-metabolizing enzymes in rats.

The induction of drug-metabolizing enzymes in rat liver was studied after subchronic administration of the new triazole antifungal agent fluconazole. The administered doses were 10, 40, and 160 mg/kg per day for 7 days. Fluconazole behaved as a high-magnitude inducer and significantly increased cytochrome P-450 concentrations already at 10 mg/kg (+42%). Cytochrome P-450 induction by fluconazole was dose dependent and reached a value of 302% of the control value at the dose of 160 mg/kg. The induction effects on cytochrome P-450 were also reflected in the drug-metabolizing enzyme activities in hepatic microsomes of pretreated rats. Fluconazole (160 mg/kg per day) preferentially induced the demethylase activities of N,N-dimethylaniline and p-nitroanisole to 258 and 281% of the control values, respectively. The detoxification enzyme UDP-glucuronosyltransferase was significantly lowered by fluconazole at the highest dose. A possible link between the induction potential and the pharmacokinetic properties of triazole antifungal agents is discussed.

Is the metabolism of alfentanil subject to debrisoquine polymorphism? A study using human liver microsomes.

The present study was designed to investigate whether the metabolism of the opiate analgesic alfentanil in humans is subject to the debrisoquine 4-hydroxylation polymorphism. The role of a specific cytochrome P-450 form, debrisoquine 4-hydroxylase, in the metabolism of alfentanil was investigated by competitive inhibition experiments over the concentration range 4-100 microM. Alfentanil was incubated with human liver microsomes in the presence of an NADPH-generating system. Alfentanil and its major metabolites were quantified in the incubates by reversed phase high-performance liquid chromatography (HPLC). Alfentanil was rapidly metabolized, yielding noralfentanil as the main metabolite. Kinetically, alfentanil metabolism occurred monophasically and the kinetic parameters were 22.8 microM for Km app and 3.86 nmol alfentanil metabolized min-1.mg protein-1 for Vm app. Debrisoquine was a weak, noncompetitive inhibitor of alfentanil metabolism and of the formation of its major metabolites, with Ki values between 2.00 and 3.21 mM. It can be concluded that alfentanil is not metabolized in vitro by the human cytochrome P-450 form involved in debrisoquine 4-hydroxylation; therefore, the in vivo disposition of the drug is most likely not affected by deficiency of this enzyme.

Assay methods for fentanyl in serum: gas-liquid chromatography versus radioimmunoassay.

In this study, two independent laboratories assessed the validity of the fentanyl radioimmunoassay (RIA) by measuring a series of spiked control serum samples and 429 serum samples from 20 patients receiving fentanyl for their anesthesia. Additionally, a gas-liquid chromatographic (GLC) method specific for the parent drug was also applied to the same serum samples. The RIA measurement of fentanyl by the two laboratories resulted in comparable values for both control samples and samples from patients in a range of 0.5-50 ng/ml. The GLC method agreed with both RIA measurements in the spiked control and patient samples. The authors' results demonstrate the validity of the RIA as a measurement technique for fentanyl in human serum samples.

Pharmacokinetics and dose proportionality of domperidone in healthy volunteers.

Domperidone is a potent gastrokinetic agent and antinauseant currently undergoing clinical trials in the United States. The bioequivalence of 20 mg of domperidone given as free-base tablets and maleate salt tablets, and the bioavailability of base and maleate tablets relative to a solution, were studied in 21 fasting men using a crossover design. Plasma samples collected for up to 48 hours were analyzed for domperidone levels, using a sensitive and specific radioimmunoassay (RIA). The absorption of domperidone was very rapid, with mean peak plasma concentration (Cmax) values of 18.8, 15.0, and 20.7 ng/mL attained at 0.9, 1.2, and 0.6 hours after the administration of base tablet, maleate tablet, and solution, respectively. The mean elimination half-life (t1/2) ranged from 12.6 to 16.0 hours. The mean oral clearance (CL/F) after the solution dose was 4,735 +/- 2,017 mL/min and the mean apparent volume of distribution (Vd/F) was 6,272 +/- 5,100 L, indicating an extensive distribution of domperidone in the body. The area under the plasma concentration-time curve (AUC) data demonstrated bioequivalence of base and maleate tablets. The relative bioavailability for base tablet and maleate tablet was 107 +/- 50% and 116 +/- 47%, respectively, of that of the solution. Dose proportionality of domperidone was also studied in 12 subjects at solution doses of 10, 20, and 40 mg. Linear correlations between the dose and Cmax and AUC values were observed. Mean CL/F remained relatively constant after doses of 10, 20, and 40 mg (5,255 +/- 3,159, 4,842 +/- 1,774, and 4,380 +/- 1,289 mL/min, respectively), indicating linear pharmacokinetics of domperidone over the dose range studied.

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 micrograms/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 (pi) and slow (alpha) distribution phases of 1.4 +/- 0.3 min and 17.7 +/- 2.6 min, respectively. The average terminal elimination (beta) half-life was 164 +/- 22 min. The average value for Vd beta was 2.9 +/- 0.2 1/kg, Vdss 1.7 +/- 0.2 1/kg and total plasma clearance 12.7 +/- 0.8 ml X kg-1 X min-1 (935 +/- 50 ml/min). In one patient, a bi-exponential 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.

Distribution of oral ketoconazole to vaginal tissue.

Plasma samples and biopsies of vaginal tissue were obtained from 23 healthy women undergoing operative sterilization, 1 to 6 h after a single oral dose of ketoconazole 200 mg. Drug concentrations in plasma and tissue, were measured by a specific gas chromatographic method. The vaginal tissue concentration averaged 2.4 times less than the corresponding plasma levels. Equilibrium between tissue, and plasma was established within 1 h after dosing, when vaginal tissue levels exceeded 1 microgram/g. Ketoconazole concentrations decayed monoexponentially over the time interval studied (1-6h), with the similar half-lives of 1.2 and 1.4 H in plasma and tissue, respectively. Following an oral 200 mg dose, a tissue concentration not less than 0.01 microgram/ml was maintained over a 12 h period. This concentration has been shown to prevent outgrowth of the invasive (pseudo) mycelial form of Candida albicans. Hence, a b.i.d. or t.i.d. dosage schedule of ketoconazole in vaginal candidosis would give continuously effective levels at the site of infection. Ketoconazole concentrations in vaginal fluid are thought to be much higher than in the tissue because of ion-trapping. The present data may explain the efficacy of oral ketoconazole in the treatment of vaginal candidosis.

Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood.

The in vitro plasma protein binding and distribution in blood of fentanyl and three analogues were studied in rats, dogs and healthy volunteers. In human plasma, 84.4% of fentanyl was bound, 92.5% of sufentanil, 92.1% of alfentanil and 93.6% of lofentanil. Plasma protein binding of the four analgesics was independent of their concentration over the whole therapeutic range. Plasma protein binding of alfentanil was much less pH dependent than that of the three other analgesics. Attention was drawn to the possible contribution of the "acute phase' protein alpha 1-acid glycoprotein (alpha 1-AGP), of lipoproteins and of blood cells to the binding of fentanyl and its analogues in blood.

Pharmacokinetics of haloperidol decanoate. A 2-year follow-up.

Plasma haloperidol levels were assayed in 181 chronic schizophrenic inpatients, who were monthly injected intramuscularly with haloperidol decanoate. Steady state levels are reached after the third monthly injection and then remain constant, being associated with a remarkably stable control of the psychotic condition. Between two subsequent injections the haloperidol levels decrease gradually by about half their initial value. The haloperidol plasma levels strongly correlate with the injected doses of the decanoate form. For a single dose of 100 mg haloperidol decanoate monthly the minimal steady state value is about 4 ng/ml.

Antiemetic effect of haloperidol in the dog as related to plasma level and dose.

A positive and highly significant correlation was found between SC dose, plasma concentration, and antiemetic effect of haloperidol in the dog. To protect dogs from apomorphine-induced emesis, a concentration of 1 ng haloperidol/ml plasma was always sufficient, whereas protection from emesis was never obtained with plasma levels lower than 0.53 ng/ml. The elimination rate of haloperidol from plasma varied from 1.53 to 2.60 among different animals. Thus, the interindividual variability to haloperidol was surprisingly low. Antiemetic effect and plasma elimination of haloperidol were not related to body weight.

Lorcainide (R 15 889), a first review.

This is a first review of lorcainide hydrochloride, a new antiarrhythmic agent with local anaesthetic activity. The antiarrhythmic actions of lorcainide are mediated by an impairment of fast sodium conductance. Pharmacologically, this drug appears effective in suppressing reentry phenomena and ectopic pacemaker activity, especially in the ventricles. Lorcainide has only negligible depressant effects on important haemodynamic parameters and its toxicity is minimal. The drug is well absorbed by the oral route and its elimination half-life is long when compared with other substances. Lorcainide-induced QRS widening is directly correlated with the plasma levels of the drug. Preliminary experience in supraventricular arrhythmias is promising but pre-excitation syndromes and the ventricular arrhythmias are the main indications for this drug since a very high response rate has been observed in these conditions. Side effects are harmless and dose-dependent, but may be clinically troublesome.

Intermittent pimozide versus fluphenazine decanoate as maintenance therapy in chronic schizophrenia.

In a double-blind trial, 34 male chronic schizophrenic day-patients or in-patients in a hostel ward continued on fluphenazine decanoate given mostly once fortnightly or were switched to pimozide, given on four days each week. Over nine months relapse rates were similar for both groups, and while fewer patients on pimozide were prescribed antiparkinsonian drugs one quarter developed buccolingual masticatory dyskinesia. Plasma pimozide levels suggested satisfactory drug compliance. Average plasma prolactin levels were within the normal rage for untreated men in one quarter of non-relapsing patients on pimozide and three quarters on fluphenazine.

Dissociation between opiate-like and antidiarrheal activities of antidiarrheal drugs.

Three synthetic antidiarrheals, diphenoxylate, loperamide and SC 27166, and two narcotics, morphine and codeine, were evaluated in rats by the intravenous and oral route for specificity and duration of their antidiarrheal, opiate-like and acute toxic effects. The activity in the castor oil test, the tail withdrawal test and the acute toxicity test was used to determine the relative antidiarrheal specificity and relative safety margins. An analysis of animal and clinical data indicate these tests to be excellent indicators of clinical usefulness and specificity. Intravenously, all five agents induced opiate-like central effects, loperamide and SC 27166 at near toxic doses only. When administered orally loperamide and SC 27166 were devoid of opiate-like central nervous system activity. Analysis of the plasma levels after oral loperamide indicated that this drug does not attain a concentration high enough to induce opiate-like central effects. All agents were effective antidiarrheals by the oral route with loperamide being the most potent (ED50 = 0.15 mg/kg), longest acting (ED50 8 hr = 1.81 mg/kg) and most specific (relative antidiarrheal specificity, 8 hr greater than or equal to 88) and having the greatest relative safety margin (8 hr = 102).