Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungaI fl uconazole.The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method.Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high eficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

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)

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.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered 3 H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, Odemethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.

The pharmacokinetics and bioavailability of domperidone, a novel gastrokinetic, were studied in healthy male subjects by comparing plasma concentrations and urinary excretion following intravenous, intramuscular, oral and rectal administration. Two oral dosage forms were studied: 10-mg tablets and a 10-mg/ml oral solution. The influence of a meal on the oral bioavailability and the dose-proportionality were also investigated. Plasma levels of intravenous domperidone could be described by a three-compartment model with a rapid distribution of 40% of the dose to a "shallow" peripheral compartment. The final elimination half-life was 7.5 hours. Peak plasma levels were reached within 30 minutes following intramuscular and oral administration and at 1-4 hours following rectal administration. Since domperidone showed an extensive first-pass elimination, AUC-values -a measure for the bioavailability- were considerably lower after oral than after parenteral administration. Equal oral and rectal doses gave a similar bioavailability. AUC-values increased proportionally with the dose over a 10-60 mg range. Cumulative urinary excretion of unchanged domperidone was proportional to corresponding AUC-values. The bioavailability was discussed in the light of the therapeutic results.