Selection of a derivative of the antiviral agent 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) with improved oral absorption.
Various diesters of 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) were screened in order to identify a derivative with improved oral absorption. The solubilities and dissolution rates decreased with increasing chain length and branching of the ester group. However, the dipropionate ester showed an anomalously faster dissolution rate. The rates of hydrolysis to DHPG in the presence of intestinal homogenates were found to increase with increasing carbon number for the straight-chain alkyl esters and decreased with branching. The shorter-chain alkyl esters were relatively more stable in intestinal homogenates than in liver homogenates. Therefore they may have a better membrane permeability than DHPG due to their intact ester group. The hydrolysis rates in human blood increased with increasing carbon number for the straight-chain alkyl esters. The dipropionate ester appeared to be the most promising derivative because of its rapid dissolution rate, slower hydrolysis in the intestine, and rapid conversion to DHPG in liver and blood.
Benjamin
E J
EJ
Institute of Pharmaceutical Sciences, Stanford Industrial Park, Palo Alto, California 94304.
Firestone
B A
BA
Bergstrom
R
R
Fass
M
M
Massey
I
I
Tsina
I
I
Lin
Y Y
YY
D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D015774:Ganciclovir / Q000031:analogs & derivatives*; D006207:Half-Life; D006868:Hydrolysis; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D010447:Peptide Hydrolases; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D010447:Peptide Hydrolases; D015774:Ganciclovir; D000212:Acyclovir