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8th Conference on Retroviruses and Opportunistic Infections
Chicago, IL - February 4 - 8, 2001
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Potential clinical relevance of drug transporters in antiretroviral pharmacology
Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:281 (abstract no. S3)
Back D, Jones K, Hennessy M, Khoo S, Meaden R, Mulcahy F, Barry M; Univ of Liverpool, UK.
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.
Keywords: AEGIS, Pharmaceutical Preparations, P-Glycoproteins, HIV Protease Inhibitors, Biological Transport, Reverse Transcriptase Inhibitors, In Vitro, Male, pharmacology, AIDS
2001-02-04
S3
Copyright © 2001 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.