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

Janneh, O., Hartkoorn, R. C., Jones, E., Owen, A., Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Davey, R., Back, D. J. and Khoo, S. H. (2008) 'Cultured CD4T cells and primary human lymphocytes express hOATPs: intracellular accumulation of saquinavir and lopinavir'. British Journal of Pharmacology, Vol 155, Issue 6, pp. 875-883.

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Abstract

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, CEMVBL, CEME1000) 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-3sulphate (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.

Item Type: Article
Uncontrolled Keywords: saquinavir lopinavir estrone-3-sulphate influx efflux montelukast lipophilicity multidrug-resistance protein-2 hiv protease inhibitors p-glycoprotein oral availability mononuclear-cells human hepatocytes drug-resistance transport brain mrp2
Subjects: QV Pharmacology > QV 38 Drug action.
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.6 Prevention and control
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1038/bjp.2008.320
Depositing User: Mary Creegan
Date Deposited: 23 Aug 2010 09:35
Last Modified: 06 Feb 2018 13:00
URI: http://archive.lstmed.ac.uk/id/eprint/815

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