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.
Hässle Cardiovascular Research Laboratories, Mölndal, Sweden.
S X
SX
Wang
T A
TA
Sutfin
C
C
Bäärnhielm
C G
CG
Regårdh
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