Effects of cholestyramine and parenteral nutrition on hepatic metabolism of lidocaine: a study using isolated rat liver perfusion.
BACKGROUND
The effect of an oral bile salt binder, cholestyramine, on parenteral nutrition-related hepatic dysfunction and lidocaine metabolism was studied in rats.


METHODS
Rats were randomly assigned to one of three treatment groups: the PN group received infusions of dextrose and amino acids; the PNC group was treated the same as the PN group, but also received oral cholestyramine; CF group animals were fed rat food and water. Lidocaine metabolism was studied in livers isolated from animals after 7 days of parenteral nutrition.


RESULTS
No differences in liver function test values of PN and PNC groups were detected compared with group fed rat food. However, lidocaine metabolism was found to be significantly reduced in both the PN and PNC groups. Significant reductions were observed in the hepatic extraction ratio (23% and 15%) and in intrinsic clearance (61% and 53%) in PN and PNC animals, respectively (p < .05). Material balance at steady state showed that recovery of lidocaine was threefold higher in the PN group and twofold higher in the PNC group than the rat food group (p < .05). Metabolite-to-drug ratios were determined for each lidocaine metabolite and this revealed significant reductions in N-dealkylation (64% and 57%) and aryl methyl hydroxylation (92% and 86%) in PN and PNC animals, respectively (p < .05).


CONCLUSIONS
Histologic findings suggest that cholestyramine feeding prevented liver dysfunction, possibly through interruption of secondary bile salt reabsorption. However, lidocaine metabolism was still impaired after cholestyramine ingestion; the impairment mechanism remains unknown.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
N
N
Zaman
Y K
YK
Tam
L D
LD
Jewel
R T
RT
Coutts
D000596:Amino Acids / Q000097:blood; D000779:Anesthetics, Local / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000837:Anion Exchange Resins / Q000494:pharmacology*; D002792:Cholestyramine Resin / Q000494:pharmacology*; D015331:Cohort Studies; D066298:In Vitro Techniques; D008012:Lidocaine / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D009994:Osmolar Concentration; D010288:Parenteral Nutrition; D010477:Perfusion; D011355:Prodrugs / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000596:Amino Acids; D000779:Anesthetics, Local; D000837:Anion Exchange Resins; D011355:Prodrugs; D002792:Cholestyramine Resin; D008012:Lidocaine