Physiologically-based pharmacokinetic modeling approach for drug disposition in human and pregnant rat
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Physiologically-based pharmacokinetic (PBPK) modeling is a useful approach to investigate the absorption, distribution, metabolism and elimination (ADME) of a compound in animals as well as humans. In this dissertation, a PBPK model was constructed to describe dose and time dependent pharmacokinetics of dichloroacetic acid (DCA) in humans. DCA is used clinically to treat metabolic acidosis and is also a potential carcinogenic contaminate in drinking water. DCA inactivates its own metabolic enzyme, glutathione transferase zeta (GSTzeta) which leads to an increased half-life after repeated dosing. GSTzeta is also a major enzyme in tyrosine catabolism and deficiency in this metabolic pathway resulting in the accumulation of intermediate metabolites is proposed as the mechanism behind DCA carcinogenicity. Therefore, quantitative evaluation of DCA pharmacokinetics and compromised GSTzeta activity following repeated dosing is critical in understanding the pharmacological and toxicological effects arising from human exposure. Nucleoside reverse transcriptase inhibitors (NRTIs) are the primary antiretroviral drugs used in highly active antiretroviral therapy (HAART), which is successful in reducing mother-to-child transmission (MTCT) of HIV. However, limited in vivo pharmacokinetic data are available for NRTI disposition in pregnant women as well as their fetuses. PBPK models are advantageous in that assessment of special physiological situations, such as pregnancy and the compounds pharmacokinetics behavior, in animal, tissues that otherwise can never been assessed in human, such as placenta and fetus. The first PBPK models describing perinatal exposure to NRTIs and the potential drug-drug interactions are reported in this dissertation. Based on the model simulations, NRTIs cross placenta through active transport, not only passive diffusion. Consequently, when co-administered, NRTI clearance from maternal tissues may be altered. Drug-drug interactions on transplacental transfer suggest a complex mechanism including up-regulated/down-regulated transport, which may be the result of multiple NRTIs transporters located on both the maternal and fetal side of the placenta. Because of the similarity between human and rat placenta, including similar transporter compositions, the interactions identified in present study may have clinical significance and thus, require careful monitoring during administration to pregnant women to protect against mother-to-child transmission (MTCT) of HIV.