Cultured CD4T cells and primary human lymphocytes express hOATPs: intracellular accumulation of saquinavir and lopinavir

Background and purpose: Drug efflux tranporters (P‐glycoprotein (P‐gp), multidrug resistance‐associated protein (MRP)) limit the cellular uptake of human immunodeficiency virus protease inhibitors but the contribution of influx transporters in cells that (over)express P‐gp or MRP is less clear. Here, we studied the expression of one influx transporter system, human organic anion‐transporting polypeptide (hOATP), in some T‐cell lines (CEM, CEM VBL , CEM E1000 ) and in peripheral blood mononuclear cells (PBMCs) and examined the effects of manipulation of influx/efflux transporters on the uptake of saquinavir and lopinavir. Experimental approach: The expression of hOATPs was studied by PCR. We used hOATP substrate or inhibitor (estrone‐3‐sulphate (E‐3‐S) or montelukast, respectively) and inhibitors of P‐gp (XR9576) and MRP (MK571 and frusemide) to study functional interactions between influx and efflux transporters in the uptake of saquinavir and lopinavir. Lipophilicity of the drugs was measured by octanol/saline partition coefficient. Key results: CEM cells, their variants and PBMCs express various hOATP isoforms, with OATP3A1 detected in all of the cells. MK571, XR9576 and frusemide increased the uptake of saquinavir and lopinavir. E‐3‐S and montelukast reduced the uptake of saquinavir and lopinavir in some, but not all, of the cells. Pretreatment of the cells with MK571, XR9576 or frusemide, followed by E‐3‐S co‐incubation reduced the cellular accumulation of saquinavir and lopinavir. Lopinavir is much more lipophilic than saquinavir. Conclusions and implications: Human OATPs, MRP, P‐gp and lipophilicity determine the cellular uptake and retention of saquinavir and lopinavir. These data may have important implications for drug–drug interactions, drug safety and efficacy. British Journal of Pharmacology (2008) 155 , 875–883; doi: 10.1038/bjp.2008.320 ; published online 18 August 2008