Long-term diabetes alters the hepatobiliary clearance of acetaminophen, bilirubin and digoxin.
The effect of insulin-dependent diabetes on hepatobiliary clearance of acetaminophen, bilirubin and digoxin was determined using Sprague-Dawley rats that were treated with a 45 mg/kg dose of streptozotocin 28 days before experimentation. Urinary excretion of acetaminophen was increased 280%, whereas biliary excretion was decreased 65% and total clearance was unchanged. Both steady-state volume of distribution and elimination half-life of acetaminophen were decreased in diabetic rats by 23 and 25%, respectively. Biliary excretion of glucuronide and sulfate conjugates was decreased by 75 and 50%, respectively, whereas parent acetaminophen excretion was unchanged. The glutathione conjugate was only detected in normal and insulin-treated rats; however, comparable levels of a cysteine conjugate were detected in bile of diabetic rats. Administration of insulin reversed the hyperglycemia and the changes in volume of distribution, elimination half-life and glutathione excretion. Other diabetes-induced alterations were unchanged. In contrast, digoxin plasma disappearance, volume of distribution and total clearance were significantly increased in diabetic rats, whereas the elimination half-life was decreased. Administration of insulin reversed the changes in serum disappearance and partially reversed the increased biliary excretion of digoxin. No differences were observed for the serum disappearance, glucuronidation or biliary excretion of bilirubin in diabetic vs. normal rats. These data indicate that insulin deficiency for 1 month can alter hepatic excretory function and the pharmacokinetics of commonly used drugs.
Watkins
J B
JB
Medical Sciences Program, Indiana University School of Medicine, Bloomington.
Sherman
S E
SE
D000082:Acetaminophen / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001663:Bilirubin / Q000493:pharmacokinetics*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics*; D005965:Glucuronates / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D007328:Insulin; D013431:Sulfates; D000082:Acetaminophen; D004077:Digoxin; D001663:Bilirubin