Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability.
The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.
Chung
Hye J
HJ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Lee
Joo H
JH
Woo
Sung J
SJ
Park
Hee K
HK
Koo
Chang H
CH
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D004355:Drug Stability; D006207:Half-Life; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D011741:Pyrimidine Nucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C493853:1-(3-fluoro-4-hydroxy-5-mercaptomethyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-2,4-dione; D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides