Interspecies comparison of the pharmacokinetics of aldose reductase inhibitors.
The pharmacokinetics of three aldose reductase inhibitors (ARIs) were evaluated in various species, including rat, dog, cynomolgus monkey, rhesus monkey, chimpanzee, and man. The three ARIs (AL01567, AL01576, and AL01750) were administered intravenously as a single dose to all species except rat, which was dosed orally with AL01750, and man, who was dosed orally with AL01567 and AL01576. Plasma drug concentrations were measured by HPLC or liquid scintillation spectrometry and various pharmacokinetic parameters (clearance, CL; Vd, volume of distribution; and t1/2) were calculated from the data. Overall the pharmacokinetics of the three compounds were quite similar, each being characterized by low CL, intermediate Vd, and long t1/2. For AL01576, mean CL ranged from 0.21 ml/min/kg in cynomolgus monkey to 0.91 ml/min/kg in dog, mean Vd from 0.66 liter/kg in cynomolgus monkey to 2.4 liters/kg in dog and man and mean t1/2 from 29 hr in dog to 72 hr in man. Mean CL of AL01567 ranged from 0.14 ml/min/kg in man to 1.4 ml/min/kg in dog, mean Vd from 0.45 liter/kg in rat to 3.5 liters/kg in dog and mean t1/2 from 22 hr in rhesus monkey to 63 hr in man. Mean CL of AL01750 ranged from 0.13 ml/min/kg in chimpanzee to 1.3 ml/min/kg in dog, mean Vd from 0.40 liter/kg in rat to 1.8 liters/kg in dog and mean t1/2 from 12 hr in rhesus monkey to 62 hr in chimpanzee. For all three drugs, CL and Vd corrected for body weight were quite similar in all species except dog, whose CL and Vd were two- to fourfold greater than the other animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Brazzell
R K
RK
Alcon Laboratories, Inc., Fort Worth, TX 76134.
Park
Y H
YH
Wooldridge
C B
CB
McCue
B
B
Barker
R
R
Couch
R
R
York
B
B
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004285:Dogs; D005449:Fluorenes / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006827:Hydantoins / Q000493:pharmacokinetics; D007908:Lens, Crystalline / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D002679:Pan troglodytes; D051381:Rats; D013012:Sorbitol / Q000378:metabolism; D013045:Species Specificity; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D005449:Fluorenes; D006827:Hydantoins; C052241:imirestat; C045887:alconil; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase