Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine

J Pharm Pharmacol. 2003 Jul;55(7):963-72. doi: 10.1211/0022357021495.

Abstract

The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2',6'-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. The local kinetics of ropivacaine and PPX were assessed from their concentration-time profiles in mucosal and serosal compartments. The permeability (P(app)) in the absorptive direction for both ropivacaine and PPX increased regionally in the order jejunum < ileum < colon. Ropivacaine was not found to be subjected to any carrier-mediated intestinal efflux. However, the CYP3A4 metabolite left the human enterocyte in a polarized manner and both the extent of CYP3A4 metabolism of ropivacaine and the extrusion of its metabolite to the mucosal chamber were more efficient in jejunum than in ileum. P-glycoprotein was probably not involved in the metabolite extrusion. No other metabolite than PPX was found. This in-vitro study with human intestinal tissues provides new mechanistic insights into regional transport and metabolism of drugs.

MeSH terms

  • Amides / metabolism
  • Amides / pharmacokinetics*
  • Anesthetics, Local / metabolism
  • Anesthetics, Local / pharmacokinetics*
  • Biological Transport, Active
  • Bupivacaine / analogs & derivatives*
  • Bupivacaine / metabolism
  • Bupivacaine / pharmacokinetics*
  • Colon / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Female
  • Humans
  • Ileum / metabolism
  • In Vitro Techniques
  • Intestinal Absorption
  • Intestinal Mucosa / metabolism*
  • Jejunum / metabolism
  • Male
  • Permeability
  • Ropivacaine

Substances

  • Amides
  • Anesthetics, Local
  • Ropivacaine
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • 2',6'-pipecoloxylidide
  • Bupivacaine