OBJECTIVES: The objectives of this study were to comprehensively assess mRNA 
expression of 84 drug transporters in human colorectal biopsies and six 
representative cell lines, and to investigate the alteration of drug transporter 
gene expression after exposure to three candidate microbicidal antiretroviral 
(ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. 
The outcome of the objectives informs development of optimal ARV-based 
microbicidal formulations for prevention of HIV-1 infection.
METHODS: Drug transporter mRNA expression was quantified from colorectal 
biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression 
was quantified in Caco-2 cells and colorectal explants after induction with 
ARVs. Data were analysed using Pearson's product moment correlation (r), 
hierarchical clustering and principal component analysis (PCA).
RESULTS: Expression of 58 of the 84 transporters was documented in colorectal 
biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the 
highest expression. No difference was noted between individual subjects when 
analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 
0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by 
immunohistochemical staining. Similarity between colorectal tissue and cell-line 
drug transporter gene expression was variable (r = 0.64-0.84). PCA showed 
distinct clustering of human colorectal biopsy samples, with the Caco-2 cells 
defined as the best surrogate system. Induction of Caco-2 cell lines with ARV 
drugs suggests that darunavir-based microbicides incorporating tenofovir may 
result in drug-drug interactions likely to affect distribution of individual 
drugs to sub-epithelial target cells.
CONCLUSIONS: These findings will help optimize complex formulations of rectal 
microbicides to realize their full potential as an effective approach for 
pre-exposure prophylaxis against HIV-1 infection.