Validated HPLC method for determination of PAT-5A, an insulin sensitizing agent, in rat plasma.

A high performance liquid chromatographic method for the determination of PAT-5A (a potent insulin sensitizer) using DRF-2095 (a thiazolidinedione) as internal standard (I.S.) is described. A 1:1 v/v ethylacetate and dichloromethane solvent mixture was used for extraction of PAT-5A from plasma. A Kromasil KR100-5C18-250A, 5 microm, 4.6 x 250 mm SS column was used for the analysis. Mobile phase consisting of sodium dihydrogen phosphate (pH 4.0, 0.05 M) and methanol mixture (25:75, v/v) was used at a flow rate of 1.0 ml/min. The eluate was monitored using a UV detector set at 345 nm. Ratio of peak area of analyte to I.S. was used for quantification of plasma samples. Using this method the absolute recovery of PAT-5A from rat plasma was > 90% and the limit of quantification was 0.05 microg/ml. The intra-day relative standard deviation (RSD) ranged from 2.19 to 4.98% at 1.0 microg/ml, 1.05 to 3.68% at 10.0 microg/ml and 3.14 to 5.08% at 50 microg/ml. The inter-day RSD were 1.6, 2.24 and 1.54% at 1, 10 and 50 microg/ml, respectively. The method was applied to measure the plasma concentrations of PAT-5A in pharmacokinetic and bioavailability studies in male Wistar rats.

Polymorphism of dextromethorphan oxidation in South Indian subjects.

One hundred fifty-six unrelated healthy South Indian subjects were phenotyped according to their ability to metabolize dextromethorphan to its O-demethylated metabolite dextrorphan. Each volunteer was administered 25 mg oral dextromethorphan hydrobromide (19.3 mg dextromethorphan). Urine was collected during an 8-hour period after drug administration and was analyzed for dextromethorphan and dextrorphan by HPLC with fluorescence detection. This analysis was performed with and without previous deconjugation. The log10 (metabolic ratio), calculated as the ratio of dextromethorphan to dextrorphan, was bimodally distributed, and it was inferred that the frequency of occurrence of poor metabolizers of dextromethorphan in South Indian subjects is 3.2%. Phenotype assignment remained the same with both methods of analysis. Furthermore, a fairly good correlation (Spearman rank order correlation coefficient [r(s)] = 0.61; P < .0001) was observed between the log-transformed metabolic ratio derived from both methods.

Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones.

A series of substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARgamma by 5a/5a maleate did not show any significant transactivation of PPARalpha or PPARgamma.

Oral bioavailability and pharmacokinetics of the new insulin sensitizer DRF-2189 in Wistar rats.

The pharmacokinetics of the new insulin sensitizing agent, DRF-2189 ([5-[4-[2-(1-indolyl) ethoxy]phenyl]methyl]thiazolidine-2,4-dione, CAS 172647-53-9) were studied in male Wistar rats following oral doses of 1, 3 and 10 mg/kg as suspension in 0.25% carboxymethylcellulose. Drug was extracted from plasma samples using a solvent mixture containing ethylacetate and dichloromethane (3:2) and analyzed by high-performance liquid chromatography with fluorescence detection. DRF-2189 was absorbed slowly, attaining maximum levels at 2-3 h, and was eliminated with a half-life (t1/2) of about 3 h. The Cmax and AUC(0-infinity) increased linearly (r2 = 0.99) with the dose, while the elimination half-life (t1/2) was independent of the dose. An intravenous pharmacokinetic study of DRF-2189 was carried out in Wistar rats at a dose of 3.0 mg/kg. The pharmacokinetic parameters AUC(0-infinity), t1/2, plasma clearance (Cl) and volume of distribution (Vd) were found to be 49.52 micrograms x h/ml, 2.99 h, 16.31 ml/h and 45.11 ml. respectively. Oral bioavailability (f) of DRF-2189 in Wistar rats was 44%. Based on pharmacokinetic studies, DRF-2189 is a good choice for further development.