Determination of a potential anxiolytic drug (CGS 20625) in human plasma by high-performance liquid chromatography.

An analytical method employing reversed-phase high-performance liquid chromatography is described for the determination of a potential anxiolytic agent in human plasma. This experimental drug candidate has potent and selective affinity for the central benzodiazepine receptor complex. The compound and internal standard are extracted from buffered plasma (pH 9.0) into ethyl acetate. The solvent is evaporated and the residue is reconstituted in chromatographic mobile phase. Separation is achieved on a 5-microns phenyl column with ultraviolet absorbance detection of the drug and internal standard at 270 nm. Recovery and reproducibility assessments indicate good accuracy (overall relative recovery of 101%) and precision (coefficients of variation from 2.0 to 11%) over the concentration range 10-1000 ng/ml. The limit of quantification for the method is 10 ng/ml. The method is suitable for pharmacokinetic analysis following the administration of 80 mg of drug to normal volunteers.

An automated method for the determination of diclofenac sodium in human plasma.

An automated method utilizing laboratory robotics has been developed for quantifying diclofenac sodium concentrations in human plasma. The robotic system aliquots the biological sample, adds the internal standard (CGP 4287), extracts the compounds from the acidified biological matrix (pH less than 2) into an organic phase (hexane-isopropyl alcohol), and concentrates the extracts for reversed-phase, high-performance liquid chromatographic (HPLC) analysis. The laboratory robot is directly interfaced to the HPLC system, and the data are automatically collected and results calculated. Separation is achieved on a 3-microns ODS (6.2-mm x 8.0-cm) column with ultraviolet (UV) detection of the drug and internal standard at 280 nm. Recovery and reproducibility assessments indicate good accuracy (overall mean relative recovery of 99.8%) and precision (coefficient of variation from 0.5 to 11.1%) over the diclofenac sodium concentration range of 5.0-1000 ng/mL, with a quantification limit of 5.0 ng/mL. The method has been successfully applied to a pharmacokinetic study in which normal volunteers received 150 mg of a prototype controlled-release formulation of diclofenac sodium.

Pharmacokinetic and pharmacodynamic comparison of an osmotic release oral metoprolol tablet and the metoprolol conventional tablet.

Four double-blind, Latin-square studies were conducted to compare the pharmacokinetics and pharmacodynamic bioavailability of metoprolol OROS (oral osmotic) and the conventional tablet (CT) of metoprolol. Metoprolol OROS (7/95 mg or 14/190 mg) was administered once daily in doses equivalent to 100 mg of metoprolol CT given once, twice, thrice, and four times a day. In all four studies, lower peak plasma concentrations and longer times to peak were observed after metoprolol OROS than after metoprolol CT, indicating a controlled-release profile for metoprolol OROS. beta-Adrenergic blockade, as measured by reductions in exercise heart rate, was lower after metoprolol OROS than after metoprolol CT, but metoprolol OROS provided a smoother and more sustained beta-blockade. All four doses of metoprolol OROS at steady state produced relative pharmacodynamic bioavailability that ranged from 87% to 104% of that produced by equivalent doses of metoprolol CT.

Automated sample preparation and chromatographic analysis: determination of CGS 10787B and related compounds.

An automated method is described for analyzing biological samples originating from CGS 10787B drug disposition studies. The method incorporates a laboratory robot to prepare plasma and urine samples and a high performance liquid chromatographic system to simultaneously analyze for CGS 10787B, as well as metabolites and drug-related compounds (CGS 12094, CGS 17000, and CGS 17001). The robot allquots the biological sample, adds an internal standard, and performs all the steps necessary for the liquid-liquid extraction and concentration of the drug and related components, while operating unattended around the clock. Recovery and reproducibility assessments indicate good accuracy and precision for the method. The limits of detection for the method are 0.2 microgram/mL in plasma and 0.5 microgram/mL in urine, for all components.

Absorption kinetics and model characteristics of orally administered pirprofen.

Pirprofen kinetics can be described by a linear two-compartment model. Absorption kinetics and model parameters were determined by the incremental method from 48 pirprofen plasma concentration-time profiles obtained after administration of single oral pirprofen doses. Statistical comparison of the results gave information on the influence of formulation, dose, and food on pirprofen absorption. The rate of absorption decreased significantly when pirprofen was administered as a capsule in comparison with a solution. The dose (200 mg compared with 100 mg) had no marked influence on the absorption rate. Food delayed absorption. Pirprofen model parameters, estimated as the median values of the results obtained from the 48 sets of data, permitted the plasma kinetics of the drug after single and repeated doses to be predicted.

Effect of pirprofen on protein binding of warfarin and tolbutamide in human plasma.

The extent of warfarin and tolbutamide binding to plasma proteins was determined with and without pirprofen by an ultrafiltration procedure employing 14C-labeled drugs. Results from in vitro studies at 37 degrees showed that the degree of binding amounted to 97.8% for warfarin and 95.6% for tolbutamide. The binding characteristics of these drugs were not altered when plasma containing either warfarin or tolbutamide at concentrations equivalent to those expected normally after therapeutic dosing were concomitantly spiked with therapeutic amounts of pirprofen. Consequently, potentiation resulting from drug displacement would not be anticipated in humans when pirprofen is administered along with warfarin or tolbutamide.

Disposition of pirprofen, a new anti-inflammatory drug.

Plasma and urine concentrations of 2-(3-chloro-4[3-pyrrolinyl]phenyl) propionic acid, pirprofen, a new nonsteroidal anti-inflammatory compound, are described for normal male volunteers receiving one or more doses of the drug. Orally administered pirprofen is rapidly and almost completely absorbed from the gastrointestinal tract, resulting in maximum plasma levels in 1 to 2 hr. Mean peak levels are 23 microng/ml after an oral pirprofen dose of 200 mg; lower doses given proportionally lower levels. Administration 1 hr after a meal slightly delays the peak plasma level, but the extent of absorption is not affected significantly. Administration of pirprofen, 150 mg, 4 times daily, or 200 mg, 3 times daily, results in nearly identical plasma levels at steady-state. Pirprofen has an apparent elimination half-life of about 7 hr. The results obtained from a 200-mg pirprofen-14C dose indicate that excretion of the drug occurs primarily by the renal route in the form of metabolites and is essentially complete within 24 hr. In urine, less than 5% of the administered dose is accounted for as unchanged drug.

Metabolism of tripelennamine in man.

Four polar metabolites were isolated from the urine of human subjects orally treated with tripelennamine, and their structures elucidated by various chemical and physical methods. One of the metabolites, which is a minor one, was identified as an N-oxide of tripelennamine, and the other three as glucuronide conjugates. One of the conjugates, which is a major metabolite, has been assigned a unique quaternary ammonium N-glucuronide structure, since it gave tripelennamine and D-glucuronic acid on incubation with beta-glucuronidase. The N-oxide, which has also been prepared synthetically, remained unchanged on similar treatment. The other two conjugates were O-glucuronides of hydroxylated derivatives, the glucuronide of hydroxytripelennamine being the principal metabolite. No desmethyltripelennamine was found in the urine, however. Hydroxylation in both cases had occurred in the pyridine ring.