Single oral dose safety, tolerability, and pharmacokinetics of PNU-96391 in healthy volunteers.

The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391.

Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients.

This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m(2) (100 microCi) [(14)C]CPT-11 in eight patients with solid tumors.

A non-radioactive iothalamate and p-aminohippuric acid high-performance liquid chromatographic method for simultaneously measuring glomerular filtration rate and renal blood flow in the rat.

A high-performance liquid chromatographic (HPLC) assay method has been developed for the quantitative determination of iothalamate and p-aminohippuric acid (PAH) concentrations in serum and urine samples in the male rat. Glomerular filtration rate (GFR) was measured as clearance of iothalamate, while effective renal blood flow (ERBF) was measured as clearance of PAH. The method is simple, rapid and sensitive and detects iothalamate and PAH in rat serum and urine following administration of bolus doses and continuous infusions of iothalamate and PAH.

Protein binding of tirilazad (U-74006) in human, Sprague-Dawley rat, beagle dog and cynomolgus monkey serum.

Determination of the serum protein binding of tirilazad across species was required to predict the pharmacokinetic behavior of this new drug. Equilibrium dialysis and ultrafiltration techniques, commonly used to study serum protein binding, were shown to be unsuitable for tirilazad due to high nonspecific binding and low aqueous solubility, resulting in unbound drug levels that were nondetectable with current analytical methodology. Ultracentrifugation appeared to offer a technique with which unbound tirilazad could be measured; however, after extensive studies, the apparent lipid partitioning behavior of tirilazad into low density and very low density lipoproteins showed that ultracentrifugation was also unsuitable for determination of the true unbound fraction of tirilazad.

Effect of ranitidine on the disposition of orally and intravenously administered triazolam.

The effect of orally administered ranitidine on the pharmacokinetic properties of orally and intravenously administered triazolam was determined. Twelve healthy males with a mean age of 35 years were enrolled in this four-way, randomized, crossover study. Each subject received a total of four treatments, each separated by one week.

Fast-LC determination of 1-methyl-1H-tetrazole-5-thiol in human plasma with column-switching sample clean-up.

A simple, fast and sensitive method for the quantitative determination of 1-methyl-1H-tetrazole-5-thiol using HPLC is reported. Samples are deproteinated by plasma water filtration and injected into a HPLC system capable of column switching and backflushing the analytical column. The limit of quantitation was determined to be 70 ng ml-1 and the limit of detection 22 ng ml-1.

Absorption of triazolam from pelleted drug-diet mixtures by the mouse: quantitation of alpha-hydroxytriazolam in urine.

The absorption of triazolam from pelleted drug-diet mixtures by mice under steady-state conditions was determined for doses up to 150 mg/kg/day by measuring alpha-hydroxytriazolam, the principal urinary metabolite of triazolam in the mouse, in urine samples collected over a 24-hour period. Following beta-glucuronide glucuronosohydrolase hydrolysis of the urine, quantitation of alpha-hydroxytriazolam was accomplished using a specific reverse-phase liquid chromatographic method which utilized UV detection at 214 nm. Assay precision was greater than 2.

Is GABA involved in analgesia?

The effect of morphine and naloxone on gamma-aminobutyric acid (GABA) concentration in discrete areas of the rat brain has been studied. Neither morphine nor naloxone had a significant effect on regional steady-state concentrations of GABA. The results have been discussed with respect to the role of GABA in pain and analgesia.