The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.

Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study-experience with 14C-labeled (R)-6-[amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a farnesyl transferase inhibitor.

Accelerator mass spectrometry (AMS) has been used in a human mass balance and metabolism study to analyze samples taken from four healthy male adult subjects administered nanoCurie doses of the farnesyl transferase inhibitor 14C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone ([14C]R115777). Plasma, urine, and feces samples were collected at fixed timepoints after oral administration of 50 mg [14C]R115777 (25.4 Bq/mg or 687 pCi/mg i.e., equivalent to 76.257 x 10(3) dpm) per subject. AMS analysis showed that drug-related (14)C was present in the plasma samples with C(max) values ranging from 1.6055 to 2.9074 dpm/ml (1.0525-1.9047 microg/ml) at t(max) = 2 to 3 h. The C(max) values for acetonitrile extracts of plasma samples ranged from 0.3724 to 0.7490 dpm/ml in the four male subjects. Drug-related 14C was eliminated from the body both in the urine and the feces, with a mean total recovery of 79.8 +/- 12.9% in the feces and 13.7 +/- 6.2% in the urine. The majority of drug-related radioactivity in urine and feces was excreted within the first 48 h. High-performance liquid chromatography (HPLC)-AMS profiles were generated from radioactive parent drug plus metabolites from pooled diluted urine, plasma, and methanolic feces extracts and matched to retention times of synthetic reference substances, postulated as metabolites. All HPLC separations used no more than 5 dpm injected on-column. The radioactive metabolite profiles obtained compared well with those obtained using liquid chromatography/tandem mass spectometry. This study demonstrates the use of AMS in a human phase I study in which the administered radioactive dose was at least 1000-fold lower than that used for conventional radioactive studies.

The metabolism and excretion of galantamine in rats, dogs, and humans.

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, O-demethylation, 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.

Strategies for absorption screening in drug discovery and development.

This review gives an overview of the current approaches to evaluate drug absorption potential in the different phases of drug discovery and development. Methods discussed include in silico models, artificial membranes as absorption models, in vitro models such as the Ussing chamber and Caco-2 monolayers, in situ rat intestinal perfusion and in vivo absorption studies. In silico models such as iDEA can help optimizing chemical synthesis since the fraction absorbed (Fa) can be predicted based on structural characteristics only. A more accurate prediction of Fa can be obtained by feeding the iDEA model with Caco-2 permeability data and solubility data at various pH's. Permeability experiments with artificial membranes such as the filter-IAM technology are high-throughput and offer the possibility to group compounds according to a low and a high permeability. Highly permeable compounds, however, need to be further evaluated in Caco-2 cells, since artificial membranes lack active transport systems and efflux mechanisms such as P-glycoprotein (PgP). Caco-2 and other "intestinal-like" cell lines (MDCK, TC-7, HT29-MTX, 2/4/A1) permit to perform mechanistic studies and identify drug-drug interactions at the level of PgP. The everted sac and Ussing chamber techniques are more advanced models in the sense that they can provide additional information with respect to intestinal metabolism. In situ rat intestinal perfusion is a reliable technique to investigate drug absorption potential in combination with intestinal metabolism, however, it is time consuming, and therefore not suited for screening purposes. Finally, in vivo absorption in animals can be estimated from bioavailability studies (ratio of the plasma AUC after oral and i.v. administration). The role of the liver in affecting bioavailability can be evaluated by portal vein sampling experiments in dogs.

Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions.

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility. Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5-hydroxytryptamine-4 receptors and which is largely without central depressant or antidopaminergic side-effects. The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated. The major in vitro metabolite of cisapride was formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the production of norcisapride. By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent. The mean apparent K(m) against cisapride was 8.6+/-3.5 microM (n = 3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 microM; therefore it is unlikely that cisapride would inhibit the metabolism of co-administered drugs. In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism.

Location of the hydroxyl functions in hydroxylated metabolites of nebivolol in different animal species and human subjects as determined by on-line high-performance liquid chromatography-diode-array detection.

Nebivolol hydrochloride (R067555), is a new antihypertensive drug. Aromatic and alicyclic hydroxylation at the benzopyran ring systems of nebivolol are important metabolic pathways. Generally, NMR is used to unambiguously assign the sites of hydroxylation. Because of the low dose rates and the extensive metabolism of nebivolol in the different species, NMR identification is not always possible, and therefore another spectroscopic technique was searched for to address this problem. UV-chromophore absorption is affected by the kind and arrangement of adjacent atoms and groups (auxochromes). The effect of these auxochromes (e.g. -NH2, -NR2, -SH, -OH, -OR and halogens) can be strongly influenced by the pH. This paper proves that HPLC at high pH combined with on-line diode-array detection is an excellent technique for the location of the hydroxyl functions in hydroxylated metabolites of nebivolol. With this technique it is possible to differentiate between glucuronidation at the automatic and aliphatic or alicyclic hydroxyl functions.

The pharmacokinetic properties of topical levocabastine. A review.

The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.

Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans.

Loperamide oxide (LOPOX) is a prodrug of loperamide (LOP). The reduction of LOPOX to LOP was investigated to provide a pharmacokinetic basis for the pharmacodynamics and improved side effect profile of the prodrug. Reduction of LOPOX was studied in vitro in gut contents, gut flora, intestinal cells, and hepatocytes. In vivo pharmacokinetics and metabolism of LOPOX and LOP were compared in the dog. LOPOX could be efficiently reduced in the gut contents of rats, dogs, and humans, with the most extensive reduction found in cecal contents. Reduction was diminished to 13% of the anaerobic LOPOX reductase activity in the presence of oxygen and to 2.5% of the original activity by heat treatment of the contents. In human ileal effluents, LOPOX reductase activity was similar in oxygen and heat sensitivity. In the rat, the cecum contained on average 89.2% of the total activity in the contents of the upper part of the intestine. In the dog, there was a gradual increase in LOPOX reductase activity from the proximal small intestine toward the cecum. In germ-free rats, the cecum contained < 1% of the activity of the small intestine. Isolated intestinal microflora of rat and dog was able to reduce LOPOX to LOP under anaerobic conditions, indicating that the microflora was primarily involved in the reduction. In its absence (i.e. in germ-free rats), reduction could still be conducted by other unknown components of the gut contents. In isolated intestinal cells, the initial rate of drug uptake was approximately 3-10 times faster for LOP than for LOPOX.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The pharmacokinetics of risperidone in humans: a summary.

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan. In poor metabolizers the half-life of risperidone was about 19 hours compared with about 3 hours in extensive metabolizers. However, becuase the pharmacology of 9-hydroxyrisperidone is very similar to that of risperidone, the half-life for the "active fraction" (risperidone +9-hydroxyrisperidone) was found to be approximately 20 hours in extensive and poor metabolizers. We found that risperidone exhibited linear elimination kinetics and that steady state was reached within 1 day for risperidone and within 5 days for the active fraction.

Plasma protein binding of risperidone and its distribution in blood.

The plasma protein binding of the new antipsychotic risperidone and of its active metabolite 9-hydroxy-risperidone was studied in vitro by equilibrium dialysis. Risperidone was 90.0% bound in human plasma, 88.2% in rat plasma and 91.7% in dog plasma. The protein binding of 9-hydroxy-risperidone was lower and averaged 77.4% in human plasma, 74.7% in rat plasma and 79.7% in dog plasma. In human plasma, the protein binding of risperidone was independent of the drug concentration up to 200 ng/ml. The binding of risperidone increased at higher pH values. Risperidone was bound to both albumin and alpha 1-acid glycoprotein. The plasma protein binding of risperidone and 9-hydroxy-risperidone in the elderly was not significantly different from that in young subjects. Plasma protein binding differences between patients with hepatic or renal impairment and healthy subjects were either not significant or rather small. The blood to plasma concentration ratio of risperidone averaged 0.67 in man, 0.51 in dogs and 0.78 in rats. Displacement interactions of risperidone and 9-hydroxy-risperidone with other drugs were minimal.

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.

The metabolism and excretion of risperidone after oral administration in rats and dogs.

The metabolism and excretion of risperidone (RIS; 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]ethyl]-6,7,8,9- tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one), a novel antipsychotic drug, were studied after single po administration of radiolabeled RIS to rats and dogs. In rats, the excretion of the radioactivity was very rapid. The predominant excretion in rat feces (78-82% of the dose) was related to an extensive biliary excretion of metabolites (72-79% of the dose), only a small part of which underwent enterohepatic circulation. In dogs, about 92% of the dose had been excreted after one week, and the fractions recovered in the urine and feces were comparable. Only a few percent of a po dose was excreted as unchanged RIS in rats as well as in dogs. Major metabolic pathways of RIS in rats and dogs were the same as those in humans. The main pathway was the hydroxylation at the alicyclic part of the 6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one moiety. The resulting 9-hydroxy-risperidone (9-OH-RIS) was the main metabolite in the excreta of dogs. In rats, the metabolism was more extensive, resulting in dihydroxy-RIS and hydroxy-keto-RIS, which were eliminated mainly via the bile. However, in male and in female rats, just as in dogs and humans, the active metabolite 9-OH-RIS was by far the main plasma metabolite. Other major metabolic pathways were the oxidative dealkylation at the piperidine nitrogen and the scission of the isoxazole in the benzisoxazole ring system. The latter pathway appeared to be effected primarily by the intestinal microflora.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption, metabolism, and excretion of risperidone in humans.

The absorption, metabolism, and excretion of the novel antipsychotic risperidone was studied in three healthy male subjects. One week after a single oral dose of 1 mg [14C]risperidone, 70% of the administered radioactivity was recovered in the urine and 14% in the feces. Unchanged risperidone was mainly excreted in the urine and accounted for 30, 11, and 4% of the administered dose in the poor, intermediate, and extensive metabolizer of debrisoquine, respectively. Alicyclic hydroxylation at the 9-position of the tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one moiety was the main metabolic pathway. The active metabolite 9-hydroxy-risperidone accounted for 8, 22, and 32% of the administered dose in the urine of the poor, intermediate, and extensive metabolizer, respectively. Oxidative N-dealkylation at the piperidine nitrogen, whether or not in combination with the 9-hydroxylation, accounted for 10-13% of the dose. In methanolic extracts of feces, risperidone, and benzisoxazole-opened risperidone and hydroxylated metabolites were detected. 9-Hydroxy-risperidone was by far the main plasma metabolite. The sum of risperidone and 9-hydroxy-risperidone accounted for the largest part of the plasma radioactivity in the three subjects. Although the debrisoquine-type genetic polymorphism plays a distinct role in the metabolism of risperidone, the pharmacokinetics of the active fraction (i.e. risperidone plus 9-hydroxy-risperidone) remained similar among the three subjects.

Comparative metabolism of flunarizine in rats, dogs and man: an in vitro study with subcellular liver fractions and isolated hepatocytes.

1. The biotransformation of 3H-flunarizine ((E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride, FLUN) was studied in subcellular liver fractions (microsomes and 12,000 g fraction) and in suspensions or primary cell cultures of isolated hepatocytes of rats, dogs and man. The major in vitro metabolites were characterized by h.p.l.c. co-chromatography and/or by mass spectrometric analysis. 2. The kinetics of FLUN metabolism was studied in microsomes of dog and man. The metabolism followed linear Michaelis-Menten kinetics over the concentration range 0.1-20 microM FLUN. 3. A striking sex difference was observed for the in vitro metabolism of FLUN in rat. In male rats, oxidative N-dealkylation at one of the piperazine nitrogens, resulting in bis(4-fluorophenyl) methanol, was a major metabolic pathway, whereas aromatic hydroxylation at the phenyl of the cinnamyl moiety, resulting in hydroxy-FLUN, was a major metabolic pathway in female rats. In incubates with hepatocytes, these two metabolites were converted to the corresponding glucuronides. 4. In human subcellular fractions, aromatic hydroxylation to hydroxy-FLUN was the major metabolic pathway. In primary cell cultures of human hepatocytes, oxidative N-dealkylation at the 1- and 4-piperazine nitrogen and glucuronidation of bis(4-fluorophenyl)methanol were observed. The in vitro metabolism of FLUN in humans, resembled more than in female rats and in dogs than that in male rats. 5. The present in vitro results are compared with data of previous in vivo studies in rats and dogs. The use of subcellular fractions and/or isolated hepatocytes for the study of species differences in the biotransformation of xenobiotics is discussed.

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)

Study of the placental transfer of cisapride in sheep. Plasma levels in the pregnant ewe, the fetus, and the lamb.

The placental transfer of cisapride, a new prokinetic agent, was studied in a sheep model. The pharmacokinetics of cisapride were studied in the lamb, the pregnant ewe, and the fetus by obtaining blood samples from chronically implanted arterial catheters. Comparable pharmacokinetic parameters were found in the lamb and the adult sheep: half-life, 1.39-1.83 hr; total plasma clearance, 1998-2160 ml/kg/hr; AUC, 92.6-100.1 ng.hr/ml. Cisapride plasma concentrations after continuous infusion were predicted correctly based on the parameters obtained after iv bolus. There was a materno-fetal transfer of cisapride following a single iv bolus administered to the mother. Cisapride crossed the placenta within 5 min and equilibrated with maternal plasma within 20 to 30 min after dosing. The average fetal-to-maternal plasma concentration ratio was 0.71. The amniotic fluid also contained measurable amounts of cisapride. The protein binding of cisapride in maternal and fetal plasma is 89.0% and 88.4%, respectively; the free fraction is 4 times larger than in humans. Cisapride crosses the ovine placental barrier. The sheep placenta is less permeable than the human placenta, but the higher free fraction of cisapride facilitates placental transfer.

Pharmacokinetics of oral antifungals and their clinical implications.

Orally active antifungals have different physicochemical and pharmacokinetic properties. Itraconazole is a broad-spectrum triazole antifungal with pronounced lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic bistriazole antifungal, fluconazole. The pharmacokinetics of itraconazole in man are characterised by good oral absorption (when taken with a meal), an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day, and biotransformation into a large number of metabolites. Distribution studies have shown that therapeutically active levels of intraconazole 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 four weeks in the stratum corneum of the skin after treatment has been stopped. These unique distribution characteristics may explain why itraconazole with relatively low plasma concentrations (but with high tissue concentrations) is as effective as fluconazole. Fluconazole interacts with cytochrome P450-dependent enzyme activities in hepatic microsomes of rats and mice. These effects in rodents are seen at plasma and liver concentrations of fluconazole comparable to those obtained in man at therapeutic dose levels. Unlike fluconazole, itraconazole does not interfere with mammalian drug-metabolising enzymes, minimising the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections.