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

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Regional transport and metabolism of roivacaine and its CYP3A4 metabolite PPX in human intestine. / Berggren, S; Lennernas, P; Ekelund, Mats; Weström, Björn; Hoogstraate, J; Lennernas, H.

In: Journal of Pharmacy and Pharmacology, Vol. 55, No. 7, 2003, p. 963-972.

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Berggren, S ; Lennernas, P ; Ekelund, Mats ; Weström, Björn ; Hoogstraate, J ; Lennernas, H. / Regional transport and metabolism of roivacaine and its CYP3A4 metabolite PPX in human intestine. In: Journal of Pharmacy and Pharmacology. 2003 ; Vol. 55, No. 7. pp. 963-972.

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TY - JOUR

T1 - Regional transport and metabolism of roivacaine and its CYP3A4 metabolite PPX in human intestine

AU - Berggren, S

AU - Lennernas, P

AU - Ekelund, Mats

AU - Weström, Björn

AU - Hoogstraate, J

AU - Lennernas, H

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

U2 - 10.1211/0022357021495

DO - 10.1211/0022357021495

M3 - Article

C2 - 12906753

VL - 55

SP - 963

EP - 972

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

SN - 0022-3573

IS - 7

ER -