The effect of renal disease on tolrestat pharmacokinetics.
Many patients with diabetes who may benefit from treatment with tolrestat, a new aldose reductase inhibitor, will have nephropathy. Therefore the effect of renal dysfunction on the pharmacokinetics of tolrestat was evaluated in eight subjects maintained on hemodialysis, 11 subjects with partial renal impairment (creatinine clearance values ranging from 14 to 80 ml/min/1.73 m2), and eight normal subjects. Each subject received a single oral dose of 200 mg tolrestat. Blood and urine samples were collected during a 48-hour period, and tolrestat concentrations were measured by HPLC. Renal dysfunction had no apparent effect on the rate of absorption or volume of distribution of tolrestat. However, tolrestat clearance was significantly reduced from 30 +/- 3 (SD) ml/hr/kg in the normal subjects to 15 +/- 5 ml/hr/kg in the subjects receiving dialysis, and tolrestat half-life was prolonged from 11 to 16 hours. Therefore a reduction in tolrestat dose is suggested for patients with severe renal impairment.
Troy
S M
SM
Wyeth-Ayerst Research, Philadelphia, PA 19101.
Hicks
D R
DR
Kraml
M
M
Conrad
K
K
Chiang
S T
ST
D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D016018:Least-Squares Analysis; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
D009281:Naphthalenes; C040550:tolrestat; D000449:Aldehyde Reductase