Received for publication November 13, 2006.
Revised March 8, 2007.
Accepted for publication March 12, 2007.

PHARMACOKINETICS AND METABOLISM OF THE PRODRUG DB289 IN RAT AND MONKEY AND ITS CONVERSION TO THE ANTIPROTOZOAL/ANTIFUNGAL DRUG DB75

Abstract

DB289 is a prodrug of DB75, an aromatic dication related to pentamidine that has demonstrated good efficacy against African trypanosomiasis, Pneumocystis carinii pneumonia and malaria, but which itself lacks adequate oral availability. The pharmacokinetics and metabolism of ¹⁴C-DB289 have been investigated in rat and monkey after oral and intravenous administration. Oral doses were well absorbed (50-70%) and effectively converted to DB75 in both species, but subject to first-pass metabolism and hepatic retention, limiting its systemic bioavailability to 10-20%. Clearance of DB289 approximated to the liver plasma flow and its large volume of distribution was consistent with extensive tissue binding. Plasma protein binding of DB289 was 97-99% in 4 animal species and humans, but that of DB75 was noticeably less and more species- and concentration-dependent. Together, prodrug and active metabolite accounted for less than 20% of the plasma radioactivity after an oral dose, but DB75 was the major radiochemical component of key organs such as brain and liver at later times and was largely responsible for the persistence of ¹⁴C in the body. The predominant route of excretion of radioactivity was via the faeces, although biliary secretion was not very extensive. HPLC and LC-MS investigations showed that the formation of DB75 from the prodrug involved the sequential loss of the two N-methoxy groups, either directly or by O-demethylation followed by reduction of the resulting oxime to the amidine. It was estimated that almost half of an oral dose of DB289 to rats and about one-third of that to monkeys was metabolised to DB75.

Key words: bioavailability, drug clearance, drug disposition, first-pass metabolism, mass spectrometry, metabolite identification, pharmacokinetics, plasma protein binding, prodrugs

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