Jp. Shaw et al., METABOLISM AND PHARMACOKINETICS OF NOVEL ORAL PRODRUGS OF 9-[(R)-2-(PHOSPHONOMETHOXY)PROPYL]ADENINE (PMPA) IN DOGS, Pharmaceutical research, 14(12), 1997, pp. 1824-1829
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.