Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children

Objective To compare the pharmacokinetics and metabolism of R (+)- and S (−)- ketorolac in children. Methods Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S (−)- and R (+)-ketorolac were measured in plasma; S (−)- and R (+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. Results Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S (−) enantiomer was 4 times that of the R (+) enantiomer. Terminal half-life of S (−)-ketorolac was 40% that of the R (+) enantiomer, and the apparent volume of distribution of the S (−) enantiomer was greater than that of the R (+) form. Recovery of S (−)-ketorolac glucuronide was 2.3 times that of the R (+) enantiomer. Conclusion The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S (−)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S (−) enantiomer suggests that stereoselective metabolism may also be a contributing factor. Clinical Pharmacology & Therapeutics (1999) 65, 382–388; doi