Kinetic disposition and placental transfer of bupivacaine enantiomers in HIV-infected pregnant women in antiretroviral therapy

• Grant number: 13/06708-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2013
• End date: January 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Marília Cristina Oliveira Souza
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Bupivacaine, an anesthetic used in obstetric anesthesia and analgesia is commercially available as a racemic mixture of (R)-(+)-bupivacaine and (S)-(-)-bupivacaine, which exhibit differences in pharmacokinetics, efficacy and toxicity. Bupivacaine is highly bound to plasma proteins, is a substrate of the efflux transporter P-glycoprotein (P-gp) and presents elimination dependent on CYP3A4. Whereas HIV infection increases the expression of P-gp in the placenta, while treatment with antiretroviral (ARV) inhibits CYP3A4 and P-gp, this study evaluates the kinetic disposition of the enantiomers of bupivacaine in pregnant women with HIV in antiretroviral therapy (ARV). In the present study, we investigated 10 pregnant women with HIV in treatment with zidovudine, lamivudine, lopinavir and ritonavir. Anesthesia or analgesia was performed using 0.5% bupivacaine with epinephrine administration of 1:200,000 in the epidural space, in doses of 2.5 to 22.5 mg. The serial blood samples were taken immediately before the time, 5, 15, 30, 45 and 60 min and 2, 4, 6, 8, 10, 12 and 14h after administration of the anesthetic bupivacaine. At delivery were also collected samples of maternal blood and cord blood, placental transfer studies. The methods developed and validated for sequence analysis of the enantiomers (+)-(R)-bupivacaine and (-)-(S)-bupivacaine and the total concentration as the free plasma concentration using LC-MS/MS spectra are consistent with the application of pharmacokinetic study in pregnant women to present the advantages of low plasma volume (200 µL), chromatographic run approximately 8 minutes, simple liquid-liquid extraction procedure, low LLQ (0.25 ng each enantiomer/mL of plasma and total concentrations of each enantiomer 0.125 ng/mL as free plasma concentration), extended linearity (0.25 to 500 ng of each enantiomer/mL of plasma and the total concentration of each enantiomer from 0.125 to 10 ng/mL as concentration of plasma free), and ensured stability in short-term studies, cycles of freezing and post-freeze and post-processing. The pharmacokinetic parameters of bupivacaine enantiomers were calculated based on total plasma concentration curves versus time using WinNonlin program. Pharmacokinetics of bupivacaine is enantioselective with plasma accumulation of enantiomer (S)-(-)-bupivacaine with AUC ratio (R)/(S) equal to 0.91 (p <0.05). The free fraction in plasma (Fu) is higher for the enantiomer (R)-(+)-bupivacaine, 9% (6-12) enantiomer compared to the (S)-(-)-bupivacaine, 6% (4 - 9) (p <0.05). The ARV treatment, including ritonavir, infers enantioselective interaction between the enantiomers of bupivacaine and P-gp placental, highlighting greater inhibition of the enantiomer (R)-(+)-bupivacaine. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OLIVEIRA SOUZA, MARILIA CRISTINA; MARQUES, MARIA PAULA; DUARTE, GERALDO; LANCHOTE, VERA LUCIA. Analysis of bupivacaine enantiomers in plasma as total and unbound concentrations using LC-MS/MS: Application in a pharmacokinetic study of a parturient with placental transfer. Journal of Pharmaceutical and Biomedical Analysis, v. 164, p. 268-275, FEB 5 2019. (13/06708-5)

OLIVEIRA SOUZA, MARILIA CRISTINA; MARQUES, MARIA PAULA; DUARTE, GERALDO; LANCHOTE, VERA LUCIA. Pharmacokinetics and Placental Transfer of Bupivacaine Enantiomers in HIV-Infected Parturient Women on Antiretroviral Therapy. Journal of Clinical Pharmacology, v. 60, n. 5, NOV 2019. (13/06708-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SOUZA, Marília Cristina Oliveira. Kinetic disposition and placental transfer of bupivacaine enantiomers in HIV-infected pregnant women in antiretroviral therapy. 2015. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.