Pharmacokinetics of paracetamol in Göttingen minipigs: in vivo studies and modeling to elucidate physiological determinants of absorption.

PURPOSE: Onset and rate of gastric emptying are important determinants of drug absorption after oral dosing. Therefore, robust estimates of these parameters are needed in physiologically based absorption models to predict reliably plasma concentration time profiles. For human and some other laboratory animals, reasonable parameterization of gastric emptying has been established. However gastric emptying is less well characterized in minipigs, a large animal model rapidly gaining importance in pharmaceutical research. METHODS: A pharmacokinetic crossover study using different dosage forms of paracetamol (intravenous and oral solution, capsule and tablet) was conducted in four male and four female Göttingen minipigs after an overnight fast. Deconvolution analysis was performed to determine the absorption kinetics. Estimated lag times and first order gastric emptying parameters were incorporated in a previously published PBPK model of the minipig and simulations verified. Postmortem assessments of minipig stomachs were made after different fasting protocols. RESULTS: Fraction of dose absorbed vs. time profiles showed high interindividual variability, comparable to human fed state absorption. Mean gastric transit times were determined to be 0.63 h, 1.36 h, and 0.73 h for solution, capsules, and tablets, respectively. Postmortem assessment confirmed that minipig stomachs were not empty after an overnight fast. CONCLUSIONS: Gastric transit times in overnight fasted minipigs are longer than those observed in humans. This is most likely caused by delayed and incomplete food emptying and further work is needed to develop feasible and effective fasting protocols for minipigs.

CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor.

The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [(3)H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED(50) equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

Impact of Solutol HS 15 on the pharmacokinetic behavior of midazolam upon intravenous administration to male Wistar rats.

The pharmacokinetic profile of midazolam (MDZ) and its major metabolites 1'-OH-midazolam (1'OH-MDZ) and 4-OH-midazolam (4OH-MDZ) was investigated in rats. MDZ was administered intravenously at 5 mg/kg either in the absence (NaCl 0.9%, control group) or in the presence of the surfactant Solutol HS 15, a weak inhibitor of cytochrome P450 3A (CYP3A) activity in vitro (Solutol HS 15-treated group). It was found that the pharmacokinetic profiles of MDZ, 1'OH-MDZ and 4OH MDZ did not differ significantly in the two dosing vehicles (P values above 0.2). MDZ exhibited a high plasma clearance (Cl) of 79 and 92 ml/min/kg (corresponding to a blood Cl of 64 and 75 ml/min/kg), a high volume of distribution (V(d)) of 4.0 and 3.6 l/kg, and an area under the plasma concentration-time curve (AUC(t0-tinf)) of 1062 and 932 h.ng/ml in the control group and in the Solutol HS 15-treated group, respectively. The amount of MDZ excreted unchanged into urine was below 0.01% with both dosing vehicles. AUC(t0-tinf) in the control group was 12.3 h.ng/ml for 1'OH-MDZ and 38.8 h.ng/ml 4OH-MDZ. In the Solutol HS 15-treated group, AUC(t0-tinf) was 14 h.ng/ml for 1'OH-MDZ and 35.4 h.ng/ml for 4OH-MDZ. The metabolite concentrations excreted into urine were below the limit of quantification. In the rat, MDZ has a high blood clearance that is limited by liver blood flow. Therefore, weak CYP3A inhibitors like Solutol HS 15 are not likely to affect the hepatic blood clearance of MDZ in vivo.