A Single-Dose Bioavailability Study of Pamidronate Disodium after Oral Administration as Encapsulated Enteric-Coated Pellets, Enteric-Coated Tablets, and a Solution to Patients with Postmenopausal Osteoporosis.

This was a pilot, single-center, single-dose, open-label, randomized three-way crossover study comparing the relative bioavailability of pamidronate disodium after oral doses of the drug administered as four capsules, each containing 75 mg enteric-coated pellets, two 150-mg enteric-coated tablets and 300 mg in solution (reference standard) in patients with postmenopausal osteoporosis. Results from seven patients are reported; five subjects completed all three phases of the study---one received solution and pellets, and another one received pellets and tablets. The onset of urinary excretion (an indicator of relative onset of oral absorption) of pamidronate disodium occurred in the first 2 h in all (except one) patients for solution and pellets, whereas the onset of urinary excretion for the tablets was prolonged and more variable. The extent of absorption was estimated in terms of percent of administered dose excreted in urine up to 72 h after dosing. The extend of absorption was highest after the pellets (mean plus minus S.D., 0.37 plus minus 0.27%), followed by the solution (0.20 plus minus 0.16%). The extent of absorption after the tablets (0.09 plus minus 0.10%) was the lowest and most variable. The poorer and more variable bioavailability of the tablets may be explained by the longer and more variable residence time of the tablets in the stomach.

Prinomide tromethamine pharmacokinetics: mutually dependent saturable and competitive protein binding between prinomide and its own metabolite.

Prinomide tromethamine, a nonsteroidal antiinflammatory drug, was orally administered at doses of 250, 500, and 1000 mg every 12 hr for 28 days to healthy male volunteers. The pharmacokinetic behavior of prinomide and its primary plasma metabolite displayed nonlinear characteristics, while those of free prinomide and its metabolite were dose proportional. The nonlinear pharmacokinetic behavior of total prinomide and p-hydroxy metabolite was found to be caused by both saturable and mutually dependent competitive Langmuir-type plasma protein binding between prinomide and its p-hydroxy metabolite. The extent of the protein interaction displayed at steady state was due to the extensive accumulation of the p-hydroxy metabolite. While ligand-protein interactions are known for xenobiotic competitors, the characteristic behavior of prinomide is the first known example to be reported for a competitive protein interaction between a xenobiotic and its own in vivo generated metabolite. The findings of this study may have implications regarding the disposition of other extensively bound nonsteroidal antiinflammatory drugs with long-lived metabolites.

Intra- and intersubject variability: mixed-effects statistical analysis of repeated doses of an angiotensin converting enzyme inhibitor, CGS 16617.

The intrasubject and intersubject variabilities for CGS 16617, an angiotensin converting enzyme inhibitor, were evaluated in an open-label, repeat single-dose bioavailability trial. Eight healthy male volunteers each received a 20-mg oral dose of CGS 16617 as an aqueous solution on four separate occasions. Components of variance were evaluated for a mixed-effects statistical model in which subjects were regarded as a random factor. While intersubject variability was statistically significant (P less than 0.05) for all pharmacokinetic variables measured, AUC, Cmax, t1/2, and tmax, its contribution to the total observed variability was relatively small for AUC, t1/2, and tmax. The proportion of variation due to intrasubject variability was 70, 19, 61, and 72% for AUC, Cmax, t1/2, and tmax, respectively. Ramifications of the large intrasubject source component of variability as related to bioavailability trials and biological variation are discussed.

Pharmacokinetic disposition of the novel atypical anxiolytic CGS 9896 in the cynomolgus monkey.

The intravenous pharmacokinetic disposition of the novel, atypical anxiolytic CGS 9896 was studied in six cynomolgus monkeys. CGS 9896 was infused at dose levels of approximately 60, 120, and 240 micrograms/h/kg for a duration of 12 h, resulting in steady-state plasma concentrations averaging 38.4, 51.8, and 124 ng/ml, respectively. The average total systemic clearance was 35.3 ml/min/kg which was independent of dose and totally attributable to nonrenal pathways. The hepatic clearance was determined to be blood flow-rate dependent and the first-pass extraction calculated as approximately 84%. Both the apparent elimination rate constant and volume of distribution exhibited dose-dependent changes. Even though the plasma protein bound fraction was high (98.6%), no concentration dependency was observed. Furthermore, no concentration dependency was observed in the plasma/blood distribution ratio indicating the observed dose-related reduction in the volume of distribution may be attributable to nonlinear tissue uptake of CGS 9896.

The pharmacokinetics of baclofen derived from intestinal infusion.

The pharmacokinetics of baclofen, a centrally acting muscle relaxant, have been elucidated in man. The pharmacokinetic disposition was determined form plasma concentration-time data and urinary recovery after the administration of rate-limiting intestinal infusions and an oral bolus dose. Based on comparisons between the plasma concentration-time profiles from the intestinal infusions and the oral bolus doses, relative regression parameter assignments were made. The intestinal absorption of baclofen after intestinal infusion was very rapid, such that baclofen disposition was well characterized by an open two-compartment pharmacokinetic model with zero-order input. Intravenous administration of baclofen was precluded from this study because of the potential for severe adverse reactions. The average distribution phase constant (alpha) was 1.29 hours-1 and the average elimination phase constant (beta) was 0.191 hours-1. Average volume of the central compartment (Vc/F), volume of the body compartment (Varea/F), systemic clearance (CL/F), and renal clearance were 28.8 L, 59.0 L, 180 ml/min, and 103 ml/min, respectively. Pharmacokinetics were dose proportional in the dose range studied. The use of these pharmacokinetic parameters as determined in normal subjects in therapeutic management is particularly relevant, because baclofen is targeted to a patient population subject to renal dysfunction.

Improved gas-liquid chromatographic method for the determination of baclofen in plasma and urine.

A simple, rapid and sensitive assay for baclofen analysis has been developed. Baclofen and the internal standard are analyzed by gas-liquid chromatography with electron-capture detection after esterification of the carboxyl group to the butyl ester and acylation of the amino group to the pentafluoropropionylamide. Recovery from biological matrixes is accomplished by ion-pair extraction. The limit of quantitation of the entire assay as stated is about 10 ng/ml baclofen in plasma.