EFFECT OF EXPERIMENTAL DIABETES-MELLITUS ON THE PHARMACOKINETICS OF ATENOLOL ENANTIOMERS IN RATS

The effect of streptozotocin-induced diabetes mellitus on the pharmacokinetics of the enantiomers of atenolol (AT) was investigated in rats 3 and 9 days after induction of the disease. Occurrence of diabetes was confirmed by a significant increase (p < 0.05) in the serum glucose concentration (mg%) of the diabetic rats compared with their respective controls in both 3- (441 +/- 66.3 versus 181 +/- 31.3) and 9- (602 +/- 133 versus 187 +/- 20.0) day diabetic groups. Creatinine clearance (CL(cr); mL/min/kg) in 9-day diabetic rats (8.98 +/- 3.02) was significantly higher than that in the controls (4.59 +/- 1.08). However, compared with the control animals, the increase in CL(cr) of the 3-day diabetic rats (8.35 +/- 1.95 versus 6.82 +/- 1.63) was not significant (p > 0.05). The changes in CL(cr) paralleled those in renal clearance (CL(r)) values of the AT enantiomers; 9-day diabetes induced a significant increase in CL(r) of the AT enantiomers (82.4 and 81.6% increase for S(-)- and R(+)-enantiomers, respectively). An increase in CL(r) values of the AT enantiomers in 3-day diabetic rats, on the other hand, did not reach statistical significance. Furthermore, a significant increase (55.4 and 52.6% for S(-)- and R(+)-AT, respectively) in the nonrenal clearance values of the AT enantiomers was observed in the 3-day, but not 9-day diabetic rats. The increases in the clearance values of the enantiomers of AT resulted in lower AUC values for the enantiomers in both the 3- and 9-day diabetic rats. Our results indicate that diabetes-induced kidney hyperfiltration in rats causes a significant increase in renal clearance of the AT enantiomers. Because AT is a recommended drug for control of hypertension in diabetic patients, further studies on the pharmacokinetics of the drug in diabetic patients are warranted.