title: Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein.
abstract: We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.
authors.affiliation: Center for Clinical Pharmacology and Therapeutics, Jichi Medical School Hospital, Minamikawachi, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Maezono
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Ohmori
authors.forename: Shuji
authors.initials: S
authors.lastname: Hishikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizuta
authors.forename: Hideo
authors.initials: H
authors.lastname: Kawarasaki
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D065095:Calcineurin Inhibitors; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003968:Diarrhea, Infantile / Q000097:blood* / Q000503:physiopathology; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood*; D007223:Infant; D008070:Lipopolysaccharides / Q000494:pharmacology; D016031:Liver Transplantation / Q000502:physiology; D019520:Living Donors; D008297:Male; D051381:Rats; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus