Background Ketorolac, a potent non-steroidal anti-in-flammatory drug, is a chiral substance. Racemic ketorolac clearance is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. We aimed to document the impact of pregnancy and postpartum on enantiomer-specific (S and R) ketorolac pharmacokinetics (PK) in young women.
Methods Observations shortly following caesarean de-livery (n=39) were pooled with data in subgroup of these women (n=8/39) four months afterwards (‘postpartum’) and with 8 healthy female volunteers, resulting in 47 un-paired and 8 paired PK estimates. All women received single intravenous bolus of ketorolac tromethamine (30 mg). Five (at 1, 2, 4, 6, 8 hour) plasma samples were collected and plasma concentrations were determined using HPLC method. Enantiomer-specific PKs were calculated using PKSolver.
Results Unpaired analysis documented that median distribution volume at steady state (Vss) for S-and R-ke-torolac was significantly higher in women following cae-sarean delivery (n=31) compared to postpartum (n=8) (S-ketorolac: 12.79 vs. 7.84 L, p=0.011; R-ketorolac: 8.96 vs. 5.86 L, p=0.001) or to healthy female volunteers (n=8).
(S-ketorolac: 12.79 vs. 9.14 L, p=0.002; R-ketorolac: 8.96 vs. 5.51 L, p<0.001). When corrected for BW, median Vss for both S-and R-ketorolac were significantly higher in women shortly following caesarean delivery compared to those in healthy female volunteers (S-ketorolac: 0.18 vs. 0.15 L/kg, p=0.037; R-ketorolac: 0.12 vs. 0.09 L/kg, p=0.001). The median clearance (CL) for S-and R-ketoro-lac was significantly higher in women following caesarean delivery compared to postpartum (S-ketorolac: 6.49 vs. 3.73 L/h, p<0.001; R-ketorolac: 2.14 vs. 1.43 L/h, p=0.002) or to healthy female volunteers (S-ketorolac: 6.49 vs. 3.60 L/h, p<0.001; R-ketorolac: 2.14 vs. 0.99 L/h, p=0.001). After taking the body size differences into account, CL to body weight (CL/BW) and CL to body surface area (CL/BSA) for S-and R-ketorolac were also higher following caesar-ean delivery compared to observations in postpartum (S-ketorolac:+33.3%, L/h·kg,+38.6%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+31.4%, L/h·m2) and in healthy female volunteers (S-ketorolac:+33.3%, L/h·kg,+48.4%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+56.8%, L/h·m2). In addition, S/R-ketorolac CL/BSA ratio was significantly higher at de-livery compared to postpartum (3.07 vs. 2.73, p=0.020). Paired PK analysis in 8 women following delivery or post-partum showed the same pattern. Finally, the simultane-ous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis.
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-ke-torolac CL and S/R-ketorolac CL ratio is higher following delivery compared to postpartum or to healthy female volunteers. For definitive physiological state-specific dos-ing recommendations in women, we encourage future repeated dosing pharmacokinetic studies in this specific population.
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