Acute Effects of Moderate Fluosol-DA Hemodilution on Hepatic Microsomal and Nonmicrosomal Metabolism in Rats

Abstract

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.

Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague-Dawley Rats

“…Table 2 also shows that CL was essentially unchanged in all groups except the 24HF group. Fluosol has been shown to induce the same rat isoenzymes (P4502B1 and P4502B2) as phenobarbital (Shrewsbury & White 1990;Shrewsbury 1992). Phenobarbital, however, appeared to have little influence on carbaryl metabolism (Knight et a1 1987).…”

“…It was, therefore, expected that Fluosol or saline haemodilution would have little effect on carbaryl elimination via the cytochrome P450 system. It has previously been reported (Shrewsbury 1992) that drug clearance is depressed soon after haemodilution but has returned to control levels by 72 h. Suggested 'transitory phenomena' include: Fluosol enhancement of hepatic drug uptake via solubilization or adsorption; Fluosol-mediated changes in the sinusoidal plasma membrane permeability; Fluosol-mediated changes in the hepatic microcirculation; Fluosol-mediated release of an endogenous substance secondary to haemodilution; or Fluosol-induced changes in metabolite disposition. There is one additional possibility that might be present in this study.…”

“…Moderate Fluosol haemodilution has been reported to induce the same cytochrome P-450 isoenzymes (P4502B 1, P4502B2) induced by phenobarbital in rats (Shrewsbury & White 1990;Shrewsbury 1992). Likewise, haemodilution has been shown to reduce plasma albumin concentrations (Shrewsbury 1991).…”