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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.

SUBMITTER: Kulo A

PROVIDER: S-EPMC5341779 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

Kulo Aida A Smits Anne A Maleškić Sanita S Van de Velde Marc M Van Calsteren Kristel K De Hoon Jan J Verbesselt Rene R Deprest Jan J Allegaert Karel K

Bosnian journal of basic medical sciences 20170221 1

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 e ...[more]

PMID: 27968707

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Project description:IntroductionViolence against women is a public health problem that poses serious consequences for victims and their environments. The healthcare system struggles to assess this phenomenon during prenatal and postpartum care because of pregnant and postpartum women's potential vulnerabilities. The research protocol presents the aims to evaluate the prevalence of violence, the period(s) in which it occurs, aggressors and forms it takes as well as to explore how violence against women is perceived among pregnant and postpartum women.Methods and analysisThis mixed methods study protocol uses an explanatory sequential design and is based on the establishment of meta-inferences that result from the combination of quantitative and qualitative approaches. Probabilistic sampling will be used to select the study participants: 584 women attending prenatal and/or postpartum care outpatient services at the University of Campinas Women's Hospital, Brazil. The quantitative approach will consist of four validated questionnaires, and the qualitative approach will use focus groups that serve to deepen the understanding of participants' views about the study topic. To create the focus groups, 72 study participants will be invited and divided into 6 groups (3 adolescents and 3 adults) based on age and pregnancy/postpartum condition. Descriptive analysis of sociodemographic characteristics and questionnaire results will be used to identify the prevalence and forms of violence experienced by women during the pregnancy-puerperal cycle, the relationships between women and their aggressors, and the existence of a history of violence. A bivariate and multivariate analysis will be performed to identify the association between sociodemographic factors and violence as an outcome. Qualitative data will be analysed through Grounded Theory to understand women's perceptions of the phenomenon studied.Ethics and disseminationThe research protocol was approved by the Research Ethics Committee of the University of Campinas, Brazil number CAAE: 13426819.1.0000.5404. The results will be disseminated to the health science community.

Project description:Aims/hypothesisThis study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), insulin response and disposition index (DI) from late pregnancy (34-37 weeks gestation, T1), to early postpartum (1-5 days, T2) and late postpartum (6-12 weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in ISOGTT, insulin response and DI.MethodsISOGTT, insulin response and DI were calculated at the three time points (T1, T2 and T3) using the results of a 75 g OGTT. Adipokines, cytokines and lipids were measured prior to each OGTT. Linear mixed-effects models were used to compare changes across each time point. Changes in ISOGTT, insulin response and DI were correlated with changes in maternal adipokines, cytokines and lipids at each time point.ResultsA total of 27 women completed all assessments. Compared with T1, ISOGTT was 11.20 (95% CI 8.09, 14.31) units higher at 1-5 days postpartum (p < 0.001) and was 5.49 (95% CI 2.38, 8.60) units higher at 6-12 weeks postpartum (p < 0.001). Compared with T1, insulin response values were 699.6 (95% CI 957.5, 441.6) units lower at T2 (p < 0.001) and were 356.3 (95% CI 614.3, 98.3) units lower at T3 (p = 0.004). Compared with T1, the DI was 6434.1 (95% CI 2486.2, 10,381.0) units higher at T2 (p = 0.001) and was 4262.0 (95% CI 314.6, 8209.3) units higher at T3 (p = 0.03). There was a decrease in mean cholesterol, triacylglycerol, LDL-cholesterol and VLDL-cholesterol from T1 to T2 (all p < 0.001), and an increase in mean C-reactive protein, IL-6 and IL-8 from T1 to T2 (all p < 0.001). Mean leptin decreased from T1 to T2 (p = 0.001). There was no significant change in mean adiponectin (p = 0.99) or TNF-α (p = 0.81) from T1 to T2. The mean maternal BMI decreased from T1 to T2 (p = 0.001) and T3 (p < 0.001). There were no significant correlations between any measure of change in ISOGTT, insulin response and DI and change in maternal cytokines, adipokines, lipids or weight from T1 to T2.Conclusions/interpretationIn women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12 weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight.Trial registrationClinicalTrials.gov NCT02082301.

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Dataset Information

Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

Publications

Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

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