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.

Novel euglycemic and hypolipidemic agents. 1.

A series of [[(heterocyclyl)ethoxy]benzyl]-2,4-thiazolidinediones have been synthesized by the condensation of corresponding aldehyde 1 and 2,4-thiazolidinedione followed by hydrogenation. Both unsaturated thiazolidinedione 2 and its saturated counterpart 3 have shown antihyperglycemic activity. Many of these compounds have shown superior euglycemic and hypolipidemic activity compared to troglitazone (CS 045). The indole analogue DRF-2189 (3g) was found to be a very potent insulin sensitizer, comparable to BRL-49653 in genetically obese C57BL/6J-ob/ob and 57BL/KsJ-db/db mice. Pharmacokinetic and tissue distribution studies conducted on BRL-49653 and DRF-2189 (3g) indicate that these drugs are well-distributed in target tissues. On the basis of euglycemic activity as well as enhanced selectivity against reduction of triglycerides in plasma, DRF-2189 (3g) has been selected for further evaluation.

Heritability estimates of blood pressure in genetically selected White Carneau pigeons.

Seven White Carneau (WC) pigeon families of the high blood pressure (HBP) line with 51 offspring and six families of the low blood pressure (LBP) line with 57 offspring were used to estimate heritability of the blood pressure trait. Pigeons from the HBP line had significantly higher systolic blood pressures than the LBP line at ages 1 through 6 months. No significant effect of age on blood pressure was observed in either the HBP line or the LBP line. Systolic, diastolic and mean arterial pressures were 155 +/- 6.4 and 122 +/- 5.7 and 139 +/- 6.1, respectively, for male parents and 163 +/- 9.3 and 125 +/- 7.1 and 143 +/- 8.3, respectively for female parents. The mid-parent mean averaged across pairs was 159 +/- 7.3 and 123 +/- 5.9, and 141 +/- 6.6, for systolic, diastolic, and mean arterial pressures, respectively. The average systolic, diastolic, and mean arterial pressures for offspring were 159 +/- 5.9, 132 +/- 5.5, and 147 +/- 5.6, respectively. Blood pressure measurements did not differ greatly between the offspring and the mid-parent mean, indicating that offspring inherit blood pressure levels similar to those of their parents. Mean heart rates were 189 +/- 12.2, 202 +/- 14.2 and 197 +/- 9.9 for the male parents, female parents and offspring, respectively. Heritability estimated by the regression of offspring on the mid-parent mean was 0.55 +/- 0.18, 0.69 +/- 0.19 and 0.61 +/- 0.18, 0.82 +/- 0.19 for systolic, diastolic and mean arterial pressure and heart rate, respectively. The results suggest that genetic factors play a significant role in influencing blood pressure in WC pigeons.

Spontaneous and diet-aggravated atherosclerosis in White Carneau pigeons genetically selected for discordant blood pressure.

White Carneau pigeons, prone to atherosclerosis, were selectively bred for either high (HBP) or low (LBP) blood pressure to study blood pressure-atherosclerosis interaction. Sixty-four HBP and 45 LBP pigeons, of both sexes and 16-30 months of age, were used to evaluate spontaneous atherosclerosis and the response to a moderately atherogenic diet. At 0 time, HBP pigeons had a greater percentage of aortic intima covered with fatty streaks and a lesser involvement with raised plaque. After 4 and 6 months of dietary treatment, the HBP pigeons with plasma cholesterol concentrations elevated only 22 and 8% above basal level responded with greater increases in the extent and severity of raised plaque whereas LBP pigeons changed little. On the average, medial thickness and medial areas of the atherosclerosis-free proximal aorta were greater in HBP compared to LBP at all times. Lower compliance of the aorta in the HBP line at 6 months (0.49 +/- 0.027 microliter/mm Hg/cm thoracic aorta) compared to LBP (0.57 +/- 0.036) suggested stiffer arterial walls in the HBP line. The findings suggest that HBP pigeons selected for increased blood pressure are more responsive to moderate hypercholesterolemia acting as a stimulus for atherosclerosis progression. The HBP pigeon line is therefore a useful animal model in which to investigate genetically derived hypertension-atherosclerosis interactions.