Avoidance of hepatic first-pass effect in the rabbit via rectal route of administration.
To assess avoidance of hepatic first-pass effect of drugs, we undertook in situ experiments using rectal administration of lidocaine in the rabbit. We also employed in situ duodenal route to estimate first-pass metabolism across the gastrointestinal mucosa. Rabbits were administered lidocaine HCl intravenously (i.v., 50 mg/20 min) and portally (i.p.v., 33.3, 16.7, 8.3 mg/20 min) and avoidance of hepatic first-pass effect (Fh) was calculated from the area under curve (AUC). Fh was about 30% and did not vary with increasing i.p.v. dose. Intravenous and i.p.v. administration was followed by duodenal (i.d.) or rectal (i.r.) administration and the absorption (fa), Fh, and avoidance of first-pass effect in the duodenal mucosal membrane (Fm) were determined. With i.d. administration, lidocaine was absorbed completely with negligible first-pass effect in the mucosa (Fm=1). On the other hand, while lidocaine was also absorbed almost completely via the i.r. route, avoidance of first-pass effect was 60%, representing twice the bioavailability via i.d. administration. On the basis of these data, assuming that the first-pass effect in the rectal mucosa was negligible, we estimate the fraction of rectal venous drainage bypassing the portal circulation and thus hepatic metabolism (fnh) to be about 40%.
Kurosawa
N
N
Hokkaido College of Pharmacy, Otaru, Japan.
Owada
E
E
Ito
K
K
D000285:Administration, Rectal; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004333:Drug Administration Routes; D007413:Intestinal Mucosa / Q000378:metabolism*; D008012:Lidocaine / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D010599:Pharmacokinetics; D011817:Rabbits; D013997:Time Factors
D008012:Lidocaine