The role of drug disposition genes for variability in the pharmacokinetics of antiretroviral drugs

Zhang, Yuan The role of drug disposition genes for variability in the pharmacokinetics of antiretroviral drugs. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

The failure of highly active antiretroviral therapy may be due to pharmacological factors such as drug transporters and metabolism enzymes. Drug transporters and metabolism enzymes played complementary roles in drug absorption, distribution, metabolism and excretion by biotransformation and counter-transport, particularly in the intestine while nuclear receptors as transcription factors regulate the expression of drug transporters and metabolism enzymes. In this thesis, a positive correlation between nuclear receptors expression and the expression of ABC transporters and OATP transporters in intestine were observed while a negative correlation was found between the gene expression of nuclear receptors and cytochrome P450 enzymes in intestine. Single nucleotide polymorphisms in genes could potentially impact on gene expression of drug transporters and metabolism enzymes. The polymorphisms of nuclear receptors were associated with the expression of ABC transporters. Drug concentrations have a high inter-individual variability in patients receiving the same dose of antiretroviral drugs, which could affect outcome of antiretroviral therapy. There are many factors that may affect plasma concentrations such as age, gender, body weight, ethnicity, genetic factors and so on. In a Ghanaian cohort, a negative correlation was found between the body weight and the EFV plasma concentration. Genetic factors such as the polymorphisms of cytochrome P450 enzymes also influenced efavirenz plasma concentrations. Meanwhile, efavirenz plasma concentrations were associated with the viral load in plasma within a UK cohort. Nanomedicine involves new and promising technologies that may enable and improve the targeted delivery of antiretroviral drugs. The permeability of lopinavir in the Caco-2 cell line was improved by formulation of nanodispersions. However, the permeability of efavirenz was decreased for all nanodispersions in MDCKII and MDCKII-ABCB5 cell lines. Comparing efficiency of efavirenz nanodispersions transcellular permeability in MDCKII and MDCKII-ABCB5 cell lines indicated that ABCB5 is able to transport efavirenz when incubated as dissolved molecule or nanodispersion. It is support by the copy number variation of ABCB5 had no relationship with EFV plasma concentrations. In summary, this thesis has attempted to determine the pharmacological factors influencing pharmacokinetics of HIV drugs, including drug transporters, metabolism enzymes and nuclear receptors. Data illustrating the factors that influence efavirenz plasma concentrations which are important for viral suppression were also generated. Furthermore, the nanodispersion technology is worthy of further study in order to improve drug delivery and drug distribution of antiretroviral drugs.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2013-01 (completed)
Uncontrolled Keywords:	HIV, Pharmacokinetics, Pharmacogenetics, Efavirenz, Lopinavir, cytochrome P450 2B6 & 3A4, ABCB1, ABCC1, ABCC2, ABCC10, PXR, CAR, Nanomedicines, Caco-2 cell lines, MDCKII cell lines
Subjects:	?? RM ??
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	14 Aug 2013 14:34
Last Modified:	16 Dec 2022 04:38
DOI:	10.17638/00009075
Supervisors:	Owen, Andrew
URI:	https://livrepository.liverpool.ac.uk/id/eprint/9075