Acute effects of moderate Fluosol-DA hemodilution on hepatic microsomal and nonmicrosomal metabolism in rats.
Fluosol has been shown to alter the disposition of several drugs immediately after its administration. Investigations in this laboratory established that the disposition of several drug markers requiring the hepatic microsomal cytochrome P-450 isoenzymes was time dependent for 72 hours. It was an additional purpose of the research to determine if the nonmicrosomal sulfation and acetylation pathways were also influenced by Fluosol hemodilution in a time dependent manner. Rats were moderately hemodiluted with Fluosol and received an intravenous dose of a drug marker 24, 48, or 72 hours after hemodilution. The formation clearance (ClF) of specific metabolites was used as the pharmacokinetic measure of a specific enzymatic activity. 3-Hydroxymethyl antipyrine ClF (phenobarbital inducible microsomal cytochrome P-450 isoenzymes) increased 300% only at 48 hours. Acetylsulfamethazine ClF (nonmicrosomal acetylation) increased 287% and 162% at 24 and 48 hours, respectively. Acetaminophen sulfate ClF (nonmicrosomal sulfation) decreased 30% only at 48 hours. Substantial evidence shows that cytochrome P-450 content is induced at 72 hours and remains induced for an unprecedented length of time by the PFCs in Fluosol. Therefore, it was unexpected that 3-hydroxymethyl antipyrine ClF was not increased at 72 hours. Several possible explanations are discussed for the unexpected findings.
Shrewsbury
R P
RP
Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001802:Blood Substitutes / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004338:Drug Combinations; D005466:Fluorocarbons / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006438:Hemodilution; D006895:Hydroxyethyl Starch Derivatives; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015238:Sulfotransferases / Q000378:metabolism
D001802:Blood Substitutes; D004338:Drug Combinations; D005466:Fluorocarbons; D006895:Hydroxyethyl Starch Derivatives; C017323:glucose, glycerol, hydroxyethyl starch, perfluorodecalin, perfluorotripropylamine, pluronic F-68, salts, yolk phospholipids drug combination; D003577:Cytochrome P-450 Enzyme System; D000123:Acetyltransferases; D014453:Glucuronosyltransferase; D015238:Sulfotransferases