Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study.

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Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV

Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study.

J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):441-9.

PubMed ID

16791115 [ View in PubMed

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Abstract

OBJECTIVE: The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes. STUDY DESIGN: Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV-RNA. RESULTS: Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log10 changes in HIV-RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA]7/[TA]7 genotypes. No relationships were identified with BCRP. DISCUSSION: Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Zidovudine	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details

Pharmaco-metabolomics

Drug	Drug Groups	Metabolite	Change	Description
Zidovudine	Approved	Bilirubin	increased	Zidovudine increases the level of Bilirubin in the blood