Title

Drug interactions and characterization of the renal disposition and secretory pathways of (--)-2'-deoxy-3'-thiacytidine (3TC) in the isolated perfused rat kidney (IPK)

Date of Completion

January 2000

Keywords

Biology, Molecular|Biology, Animal Physiology|Chemistry, Biochemistry|Chemistry, Pharmaceutical

Degree

Ph.D.

Abstract

The compound (−)-2-deoxy-3-thiacytidine (3TC) is used in the treatment of the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV). Although 3TC is one of the more effective antivirals, viral resistance may occur with monotherapy. To retain therapeutic benefit and avoid viral resistance, combination therapy is utilized. Therefore, 3TC is necessarily coadministered with other therapeutic agents for primary infection and opportunistic sequelae. ^ The aims of this research were three-fold: (1) to determine the dose dependency of 3TC renal clearance; (2) to identify involvement of nucleoside transporters in the renal disposition of 3TC; and (3) to investigate the effects of nine clinically relevant compounds on 3TC renal disposition. All experiments were conducted using the isolated perfused rat kidney (IPK) as a model of human renal disposition. ^ The clearance of 3TC demonstrated dose dependence and exhibited evidence of active secretion and reabsorption. Observations were consistent with high-capacity, low-affinity secretion and low-capacity, high-affinity reabsorption. A model with two hyperbolic terms described the observed excretion ratio data as a function of perfusate 3TC concentration, and predicted the observed urinary excretion rate data. ^ The involvement of a nucleoside transporter in the renal disposition of 3TC was not supported. Following inhibition of the classical organic anion and cation transporters, thymidine was unable to effect a change in the observed reabsorption of 3TC. The inability of thymidine to inhibit 3TC reabsorption indicated that nucleoside transporters of the proximal tubule brush border did not influence the renal disposition of 3TC. ^ Four of nine therapeutic compounds at clinically relevant concentrations caused statistically significant changes in the disposition of 3TC. Investigational drug 1 and lobucavir decreased the net secretion of 3TC, while investigational drug 2 and ribavirin increased the net secretion of 3TC. Although statistically significant in IPK, in humans these drug interactions may not be clinically significant. Therefore, clinical investigations of these four compounds in combination with 3TC are warranted. ^