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Interactions of Tenofovir, Lamivudine, Abacavir and Didanosine in Primary Human Cells
Department of Biomolecular and Sport Sciences, Coventry University, Priory Street, Coventry CV1 5FB, UK
Department of Pharmacology and Therapeutics, The University of Liverpool, 70, Pembroke Place, Block H, First Floor, Liverpool. L69 3GF, UK
* Author to whom correspondence should be addressed.
Received: 26 May 2011; in revised form: 8 June 2011 / Accepted: 21 June 2011 / Published: 22 June 2011
Abstract: Certain triple nucleoside/tide reverse transcriptase inhibitor (NRTI) regimens containing tenofovir (TDF) have been associated with rapid early treatment failure. The mechanism is unknown, but may be at the level of drug transport. We measured the lipophilicity of the drugs [3H]-lamivudine (3TC), -didanosine (ddI), -TDF and -ABC. Peripheral blood mononuclear cells (PBMCs) were used to evaluate drug–drug interactions at the level of drug transport. PBMCs were measured for the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP) by flow cytometry. The rank order of the lipophilicity of the drugs were ABC>>>3TC³ddI>TDF. The accumulation of [3H]-3TC, -ddI and -TDF were temperature sensitive (suggesting facilitated transport), in contrast to [3H]-ABC. ABC reduced the accumulation of [3H]-3TC, and cell fractionation experiments suggested this was mainly in membrane-bound [3H]-3TC. ABC/TDF and ABC/ddI increased the accumulation of [3H]-3TC and 3TC/TDF also increased the accumulation of [3H]-TDF. In contrast, none of the NRTI/NtRTI incubations (alone or in combination) altered the accumulation of [3H]-ABC and -ddI. PBMC expression of P-gp, MRP1 and BCRP were detected, but none correlated with the accumulation of the drugs. The high failure rates seen with TDF, ABC and 3TC are not fully explained by an interaction at transporter level.
Keywords: tenofovir; lamivudine; abacavir; didanosine; drug transport
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Janneh, O.; Khoo, S.H. Interactions of Tenofovir, Lamivudine, Abacavir and Didanosine in Primary Human Cells. Pharmaceutics 2011, 3, 326-337.
Janneh O, Khoo SH. Interactions of Tenofovir, Lamivudine, Abacavir and Didanosine in Primary Human Cells. Pharmaceutics. 2011; 3(2):326-337.
Janneh, Omar; Khoo, Saye H. 2011. "Interactions of Tenofovir, Lamivudine, Abacavir and Didanosine in Primary Human Cells." Pharmaceutics 3, no. 2: 326-337.