Contribution of the intestine to the first-pass metabolism of felodipine in the rat.
The systemic availability of intraduodenally (i.d.) administered felodipine in the rat is about 10%. The purpose of this study was to determine to what extent intestinal metabolism contributes to the first-pass elimination of felodipine in the rat. Four different types of experiments were performed. 1) [3H]Felodipine was given i.v. and i.p.; 2) the uptake of i.p. administered [3H]felodipine by the lymph was studied for 3 hr after dosing; 3) portal blood was collected quantitatively for 40 min after i.d. administration of [3H]felodipine; and 4) the in vitro metabolism of felodipine was studied in intestinal cell suspensions. The mean bioavailability of the i.p. dose was approximately 48%. The uptake via the lymph was negligible as an insignificant amount of the radioactive i.p. dose was recovered in lymph from a main lymph vessel in the peritoneal cavity. An average of 21 +/- 12% of given radioactive dose was recovered in portal blood during the first 40 min after i.d. dosing. The recovered radioactivity was to 40 to 70% due to felodipine and 9 to 16% was due to dehydro-felodipine. These results indicate that substantial first-pass elimination occurs in the intestine of the rat. Further support for gastrointestinal metabolism of felodipine in the rat was obtained from incubations with intestinal cells.
Wang
S X
SX
Hässle Cardiovascular Research Laboratories, Mölndal, Sweden.
Sutfin
T A
TA
Bäärnhielm
C
C
Regårdh
C G
CG
D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D015736:Felodipine; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009568:Nitrendipine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011168:Portal System / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002121:Calcium Channel Blockers; D009568:Nitrendipine; D015736:Felodipine