Species-dependent and site-specific intestinal metabolism of ester prodrugs.
In order to select a species for drug absorption studies of ester prodrugs and to identify a possible absorption window with low esterase activity and hence increased absorption of the ester prodrug, the esterase activity was investigated in homogenates from various intestinal segments of different species. p-Nitrophenyl acetate and tenofovir disoproxil [bis(POC)-PMPA] were used as substrates for esterases. p-Nitrophenyl acetate is a model substrate for esterase activity, while tenofovir disoproxil (fumarate salt) is an ester prodrug of the potent antiviral nucleoside phosphonate analogue tenofovir. As esterase-mediated degradation during transepithelial transport may be a limiting factor for its oral absorption, targeting the prodrug to a region of the intestine with lower esterase activity may lead to an increase in oral absorption of the prodrug. The results obtained with p-nitrophenyl acetate and tenofovir disoproxil showed both a site-specific (duodenum > or = jejunum > ileum > or = colon) and species-dependent (rat > man > pig) degradation in intestinal homogenates. Degradation of tenofovir disoproxil in homogenates from Caco-2 monolayers (0.016+/-0.003 nmol. s(-1). mg protein(-1)) was low compared to its degradation in homogenates from human ileum (0.177+/-0.052 nmol. s(-1). mg protein(-1)). Rat ileum appears to be a suitable model to evaluate the influence of esterase activity on the oral absorption of the ester prodrug, as the degradation rate for tenofovir disoproxil (0.245+/-0.054 nmol. s(-1). mg protein(-1)) in rat ileum was similar to degradation in human ileum. The results also suggest that colon targeting may be a useful strategy to reduce the esterase-mediated degradation of ester prodrugs, hence resulting in a possible increase in their oral absorption.
Van Gelder
J
J
Laboratorium voor Farmacotechnologie en Biofarmacie, Campus Gasthuisberg, K.U. Leuven, Belgium.
Shafiee
M
M
De Clercq
E
E
Penninckx
F
F
Van den Mooter
G
G
Kinget
R
R
Augustijns
P
P
D000818:Animals; D018938:Caco-2 Cells; D004952:Esters / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000493:pharmacokinetics; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013552:Swine
D004952:Esters; D009596:Nitrophenols; D011355:Prodrugs; C008642:4-nitrophenyl acetate