caa a22 4500 477126618 CHVBK 20180405111651.0 cr unu---uuuuu 170330e19971201xx s 000 0 eng 10.1023/A:1012108719462 doi (NATIONALLICENCE)springer-10.1023/A:1012108719462 Metabolism and Pharmacokinetics of Novel Oral Prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in Dogs [Elektronische Daten] [Jeng-Pyng Shaw, Cathy Sueoka, Reza Oliyai, William Lee, Murty Arimilli, Choung Kim, Kenneth Cundy] Purpose. A series of prodrugs designed to enhance the oral bioavailability of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA; 1) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) esters 3-9. The in vitro biological stability andin vivo pharmacokinetics of these prodrugs were evaluated to support selection of a prodrug candidate for clinical evaluation. Methods. The in vitrobiological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma and liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detection. Oral bioavailability of PMPA from each prodrug was determined in fasted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were compared to historical data for intravenous PMPA. Results. All prodrugs were rapidly hydrolyzed in dog plasma and tissues (t1/2 < 60 min). In 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 ranged from 16.0% to 30.7% and PMPA was the major metabolite formed. Conclusions. There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxycarbonyloxymethyl) PMPA 8 (t1/2 < 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation. Plenum Publishing Corporation, 1997 prodrug nationallicence 9-[(R)-2-(phosphonomethoxy)propyl]adenine nationallicence antiretroviral drug nationallicence oral bioavailability nationallicence Shaw Jeng-Pyng Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Sueoka Cathy Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Oliyai Reza Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Lee William Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Arimilli Murty Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Kim Choung Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Cundy Kenneth Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1824-1829 0724-8741 14:12<1824 1997 14 11095 https://doi.org/10.1023/A:1012108719462 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012108719462 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shaw Jeng-Pyng Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Sueoka Cathy Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Oliyai Reza Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Lee William Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Arimilli Murty Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Kim Choung Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 700 1- Cundy Kenneth Gilead Sciences, Inc., 353 Lakeside Drive, 94404, Foster City, California aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1824-1829 0724-8741 14:12<1824 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer