Characterizing the mechanism of differential pharmacokinetic disposition of two structurally similar nucleoside reverse transcriptase inhibitors, zidovudine and didanosine
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Lee, Sung-Hack. Characterizing the mechanism of differential pharmacokinetic disposition of two structurally similar nucleoside reverse transcriptase inhibitors, zidovudine and didanosine. Retrieved from https://doi.org/doi:10.7282/T3GB24DP
DescriptionThe differential contributions of efflux transporters and metabolizing enzymes to the disposition of zidovudine (azidothymidine, AZT) and didanosine (dideoxyinosine, ddI) were investigated using murine and human cells, mouse kidney slices, and mice. Cellular transport, transport in mouse kidney slices, brain uptake, and urinary excretion of AZT and ddI were investigated.
Fumitremorgin C (FTC), a breast cancer resistance protein (BCRP) specific inhibitor), increased AZT accumulation, but had little or no effect on ddI accumulation in either HEK-R482 or in J774. Involvement of BCRP was investigated by comparing results in Mock- and BCRP- transfected cells, and confirmed by repeating the studies after silencing BCRP using siRNA. MK-571, a MRP family inhibitor, blocked the efflux of AZT and ddI in murine and human cells. Silencing MRP3 and MRP4 attenuated the efflux of AZT while silencing MRP1 attenuated ddI efflux. The effect of blocking efflux transporters was found to be minor as compared to inhibition of metabolizing enzymes. The major form of AZT deposited inside murine cells was AZT-MP, while the major form found inside human cells was AZT-TP. MK-571 abolished the efflux of AZT-MP in both murine and human cells. However, the efflux of AZT, ddI and their metabolites was not affected by FTC. Application of MK-571 also decreased the efflux of GAZT and ddI in kidney slices. The urinary excretion of AZT and ddI with MK-571 in mice was measured. MK-571 did not cause any significant changes in the urinary excretion of AZT, ddI, or their metabolites between the MK-571 untreated and treated groups.
Collectively, the results of these studies indicate that AZT and ddI are substrates of BCRP and MRPs, however since their effects are limited in in situ and in vivo situation they appear to be relatively minor players in the overall disposition of these drugs.