METABOLISM AND PHARMACOKINETICS OF NOVEL ORAL PRODRUGS OF 9-[(R)-2-(PHOSPHONOMETHOXY)PROPYL]ADENINE (PMPA) IN DOGS

Purpose. A series of prodrugs designed to enhance the oral bioavailabi lity of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]ade nine (PMPA; I) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) eaters 3-9. The in vitro biological stability and in vivo pharmacokinetics of these pr odrugs were evaluated to support selection of a prodrug candidate for clinical evaluation. Methods. The in vitro biological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma a nd liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detecti on. Oral bioavailability of PMPA from each prodrug was determined in f asted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were co mpared to historical data for intravenous PMPA. Results. All prodrugs were rapidly hydrolyzed in dog plasma and tissues (t(1/2) < 60 min), T n fasted beagle dogs, bis-[(pivaloyloxy)methyl] PMPA (bis-POM PMPA) 2 had the highest oral bioavailability as PMPA (37.8 +/- 5.1%). The oral bioavailabilities of PMPA from bis(alkoxycarbonyloxymethyl) esters ra nged from 16.0% to 30.7% and PMPA was the major metabolite formed. Con clusions. There was a correlation between oral bioavailability and int estinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r(2 ) = 0.96). Lipophilicity (log P) was not a good predictor of oral bioa vailability, The most labile prodrugs in dog intestinal homogenates, b is-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxycarbonyl oxymethyl) PMPA 8 (t(1/2) < 5 min) had the lowest oral bioavailabiliti es. Based on good oral bioavailability (30.1%), chemical and intestina l stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.