title: Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.
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.
authors.affiliation: Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina. aida.kulo@mf.unsa.ba.
authors.forename: Aida
authors.initials: A
authors.lastname: Kulo
authors.forename: Anne
authors.initials: A
authors.lastname: Smits
authors.forename: Sanita
authors.initials: S
authors.lastname: Maleškić
authors.forename: Marc
authors.initials: M
authors.lastname: Van de Velde
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Calsteren
authors.forename: Jan
authors.initials: J
authors.lastname: De Hoon
authors.forename: Rene
authors.initials: R
authors.lastname: Verbesselt
authors.forename: Jan
authors.initials: J
authors.lastname: Deprest
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D001835:Body Weight; D016022:Case-Control Studies; D002585:Cesarean Section; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D020910:Ketorolac / Q000097:blood / Q000493:pharmacokinetics*; D020911:Ketorolac Tromethamine / Q000097:blood / Q000493:pharmacokinetics*; D049590:Postpartum Period; D011247:Pregnancy; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020911:Ketorolac Tromethamine; D020910:Ketorolac