Abstract
Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.
Highlights
Ketorolac is a potent nonsteroidal anti-inflammatory drug. It is a chiral substance consisting of S (−) and R (+) enantiomers. These ketorolac enantiomers come in equal portions [1], pharmacological activity, being almost exclusively attributed to S-ketorolac [2,3,4,5,6], makes enantiomer-specific ketorolac pharmacokinetics (PKs) clinically relevant
Enantiomer-specific ketorolac PKs were calculated in women shortly following cesarean delivery (n = 39)
PK estimates in 31 women shortly following cesarean delivery were compared to the observations in eight women in the postpartum period and in eight healthy female volunteers (Table 1)
Summary
Ketorolac is a potent nonsteroidal anti-inflammatory drug. It is a chiral substance consisting of S (−) and R (+) enantiomers. These ketorolac enantiomers come in equal portions [1], pharmacological activity, being almost exclusively attributed to S-ketorolac [2,3,4,5,6], makes enantiomer-specific ketorolac pharmacokinetics (PKs) clinically relevant. Stereoselectivity has been described for ketorolac binding to plasma albumin as well as for ketorolac metabolism. Stereoselective binding to plasma albumin, which is lower for S- (98.4%) than for R-ketorolac (99.2%) [3], can explain enantiomer-specific PK differences [7,8]. Stereoselective ketorolac metabolism by uridine-diphosphate-glucuronosyltransferase (UGT) 2B7 has been documented as higher for S- than for R-ketorolac [8,9]. The S/Rketorolac area under the curve (% AUC) after intravenous (IV)
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