Optimization of the local inhibition of intestinal adenosine deaminase (ADA) by erythro-9-(2-hydroxy-3-nonyl)adenine: enhanced oral delivery of an ADA-activated prodrug for anti-HIV therapy.

Previous in situ perfusion studies in rat ileal segments have demonstrated that high concentrations (>40 microg/mL) of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), a semitight binding inhibitor of adenosine deaminase (ADA), are effective in completely inhibiting the intestinal metabolism of 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), an ADA activated prodrug of the anti-HIV agent 2', 3'-dideoxyinosine (ddI) designed for improved targeting to the central nervous system. However, the intestinal absorption of EHNA results in complete inhibition of the ADA activity in the mesenteric blood draining the isolated intestinal segment being perfused and may lead to complete inhibition of ADA present in the systemic circulation and other sites, an unacceptable outcome since bioconversion in the target tissue is required for prodrug efficacy. This study examines the feasibility of locally inhibiting ADA present in the intestinal wall using EHNA to increase the intestinal absorption of 6-Cl-ddP. Transport experiments conducted in isolated ileal segments from mesenteric cannulated rats using perfusate containing prodrug and various concentrations of EHNA demonstrated that a 0.1 microg/mL logarithmic mean lumenal concentration of EHNA was effective in increasing the intestinal bioavailability of Cl-ddP to > 90%. Intestinal uptake parameters for EHNA and pharmacokinetic parameters generated in vivo in chronically catheterized rats given intravenous infusions ranging from 12.5 to 310 microg/kg/min were used to demonstrate that <10% of systemic ADA would be inhibited at steady state using the optimal perfusate concentration of EHNA. Thus, in continuous perfusions it is possible to increase the intestinal bioavailability of 6-Cl-ddP to >90% with minimal (<10%) inhibition of systemic ADA. Local inhibition of enzymes may be an effective strategy to increase the oral bioavailability of tissue enzyme-activated prodrugs or other drugs which may also be substrates for intestinal enzymes.