S3   Potential Clinical Relevance of Drug Transporters in Antiretroviral Pharmacology

D. Back* ¹ , K. Jones ¹ , M. Hennessy ² , S. Khoo ¹ , R. Meaden ¹ , F. Mulcahy ³ , M.Barry ^2
1Univ. of Liverpool, UK;²Trinity Coll., Dublin, Ireland; and³St James’ Hosp., Dublin, Ireland

Penetration of antiretrovirals into all HIV-infected cells and compartments at concentrations sufficient for antiviral effect is essential if drugs are to effectively inhibit replication and prevent re-emergence of virus in plasma. P-glycoprotein (P-gp ) and multidrug resistance protein (MRP1) can actively extrude protease inhibitors (PIs) from cells. Enterocyte P-gp limits oral bioavailability, whereas P-gp present in brain and testis is probably a critical factor in relation to these HIV sanctuary sites in the body. But P-gp (and MRP) is also functionally expressed in several subclasses of lymphocytes and thereby has the potential to reduce the intracellular concentration of PI (this being the ultimate determinant of antiviral effect). There is currently a hug research effort to elucidate the pharmacological role of efflux transporters in relation to the disposition of many therapeutic agents; this is certainly true for antiretrovirals with studies focussed on mechanisms, clinical relevance and potential strategies to interfere with transporter function. Our in vitro studies in cell lines expressing P-gp and MRP-1 have demonstrated that both initial rates of uptake and steady-state intracellular accumulation of PIs are markedly altered compared to parental cells. Overexpression of multidrug transporters significantly reduces accumulation of PIs which has clear implications for the acquisition of viral resistance. In vivo , we are determining intracellular and plasma PK of individual PIs and attempting to link this with transporter expression. The potential (and limitations) for targeted inhibition of transporters will be discussed.