The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat.

Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDMI) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution is not expected to influence the hepatic P4502D6 activity in man. However, Fluosol may have marked influences on the apparent volumes of distribution of basic drugs that bind to alpha-1-acid-glycoprotein.

The effect of moderate haemodilution with Fluosol-DA or Hespan on the nonmicrosomal acetylation of sulphadimidine in the rat.

The effects of Fluosol-DA (Fluosol) and Hespan haemodilution on the nonmicrosomal acetylation of sulphadimidine were studied in male rats. Fluosol increased the acetylsulphadimidine percent excreted in urine, the metabolic formation rate constant (kf), and the formation clearance (CLF) for 72 h after haemodilution without any significant changes in the sulphadimidine apparent volume of distribution (Vd) or total body clearance (CL). Hespan haemodilution increased the acetylsulphadimidine percent excreted in urine only at 48 h while significantly decreasing the sulphadimidine clearance, urinary excretion rate constant (ku), and renal clearance (CLR) for 72 h. The enhanced N-acetyltransferase activity after Fluosol haemodilution may have therapeutic consequences for concomitantly given drugs metabolized by this enzyme.

Influence of the method of fluosol-DA administration on antipyrine metabolism in the rat.

Antipyrine disposition has been determined in the rat following administration of Fluosol-DA by an intravenous infusion without blood removal or a haemodilution procedure, and compared with data from sham haemodiluted rats (blood removed and returned) and control rats which only received antipyrine. Antipyrine total body and renal clearance and the formation clearance of two of its metabolites were affected differently at 48 h by the pretreatments. The haemodilution procedure enhanced, the sham haemodilution reduced, and the intravenous infusion had no effect on the phenobarbitone inducible cytochrome P450 isoenzyme activity.

The in-situ absorption of antipyrine as a measure of intestinal blood flow in Fluosol-DA haemodiluted rats.

The effect of moderate Fluosol-DA haemodilution on intestinal blood flow has been investigated in the rat. Antipyrine in-situ intestinal absorption is blood flow limited, and did not alter 0.5, 24, 48, or 72 h after haemodilution with 40 mL kg-1 Fluosol. Thus the intestinal blood flow rate is maintained as part of the physiological response to ensure adequate perfusion of the vital organ.

Evaluation of cytochrome P-450 mediated metabolism of antipyrine in the rat at different extents of fluosol-DA hemodilution.

Two reports of antipyrine disposition in rats after hemodilution with 20, 40, or 80 ml/kg of Fluosol-DA are evaluated to determine if the extent of hemodilution influenced cytochrome P-450 mediated antipyrine metabolism. Alterations in antipyrine clearance (Cl) and 3-hydroxymethylantipyrine (3OHME) formation clearance (ClF) show that the extent of Fluosol hemodilution influences both the time and pattern of change in cytochrome P-450 isoenzyme activity. Alterations in antipyrine Vd had no consistent pattern with different extents of hemodilution.

The effect of moderate hemodilution with fluosol-DA or normal saline on acetaminophen disposition in the rat.

Hemodilution with 40 ml/kg of Fluosol or saline reduced the acetaminophen Vd and the acetaminophen sulfate ClM at 48 or 72 h, respectively. Fluosol hemodilution increased the acetaminophen renal excretion at 24 and 72 h. But at 48 h, Fluosol hemodilution either inhibited the renal secretion of acetaminophen or enhanced its reabsorption.

The effect of varying extents of Fluosol-DA or normal saline haemodilution on the dose dependent kinetics of phenytoin in the rat.

Phenytoin kinetics were determined in rats in which the blood was moderately haemodiluted with 20 or 40 mL kg-1 of Fluosol-DA or normal saline. Rats received one of three intravenous phenytoin doses (10, 40, 50 mg kg-1) 0.5, 24, 48, or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with either 20 or 40 mL kg-1 of Fluosol or saline had no influence on the dose-dependent kinetics of phenytoin. Haemodilution with 40 mL kg-1 of Fluosol decreased the half-life of phenytoin's major metabolite, HPPH, after a 50 mg kg-1 dose. Neither Fluosol nor saline haemodilution affected the normal delay in biliary cycling of HPPH.

The effect of moderate fluosol-DA hemodilution on gender specific metabolism of antipyrine.

Antipyrine metabolism was determined after hemodilution with 40 ml/kg of Fluosol in conscious, unrestrained female and male rats. Rats received an intravenous antipyrine dose (20 mg/kg) 24, 48, or 72 hours after hemodilution and the pharmacokinetic parameters were compared to non-exchanged control animals. Changes in the plasma disposition parameters were the same in both genders but the specific characteristic of a greater half-life in female rats was retained. A significant increase in antipyrine clearance was found at 48 hours after hemodilution. 3OHME clearance was increased in both female and male rats but 4OH clearance was increased only in female rats at that time. The data also suggested that the Fluosol emulsion induced a different microsomal enzyme activity change than its most studied component, perfluorodecalin.

The effect of moderately severe hemodilution with Fluosol-DA on cytochrome P-450 mediated antipyrine metabolism.

Antipyrine metabolism was determined in conscious, unrestrained rats after isovolemic hemodilution with FluosolR-DA. Rats received an intravenous antipyrine dose (20 mg/kg) 0.5, 24, 48, or 72 hours after hemodilution and the pharmacokinetic parameters were compared to non-exchanged control (CONT) animals. Antipyrine clearance (Cl) was significantly decreased at 0.5 and 72 hours after hemodilution. Hemodilution did not significantly alter the antipyrine apparent volume of distribution (Vd) for 48 hours; however, Vd was significantly decreased by 60% at 72 hours. The cytochrome P-450 mediated formation of 3OHME and 4OH was significantly increased at 48 and 72 hours due to an increased metabolite formation rate constant (kf) and not an enhanced metabolic clearance (Clm).

Some insights into the variations in antipyrine pharmacokinetics in the rat.

Antipyrine plasma disposition and urinary metabolic profile studies conducted in this laboratory between 1984 and 1987 are reported. A comparison of this data is made to a previous report of temporal variation in antipyrine plasma disposition parameters over a 18 month period. It is suggested that antipyrine plasma disposition parameters may not be sensitive indicators of temporal variation, but that variation in the metabolic profile might provide such evidence.

The effect of varying percentages of haemodilution with fluosol-DA or normal saline on antipyrine metabolism in the rat.

Antipyrine disposition and metabolism in conscious, unrestrained rats after 25 or 50% haemodilution with Fluosol or normal (0.9% NaCl) saline is reported. Rats received an intravenous antipyrine dose (20 mg kg-1) 0.5, 24, 48, or 72 h after haemodilution and its pharmacokinetic parameters have been compared with non-exchanged control animals. Haemodilution 25% with Fluosol initially depressed antipyrine metabolism for 24 h by decreasing the antipyrine urinary excretion rate constant and the formation rate constants of 4-hydroxyantipyrine (4-OH) and 3-hydroxymethylantipyrine (3-OHME). Metabolism was then increased for 48 and 72 h with a slight increase in all rate constants. Haemodilution 50% with Fluosol produced a similar pattern but with significant increases in the 3-OHME formation rate constant found at 48 and 72 h. Haemodilution 25% with saline reduced 4-OH formation for 48 h. Haemodilution 50% with saline significantly reduced antipyrine urinary excretion at all times. After a significant increase in the 4-OH and 3-OHME formation rate constants at 24 h following 50% haemodilution with saline, the rate constants were significantly decreased at 48 and 72 h. Haemodilution 25% with Flusol significantly reduced the antipyrine Vd at 0.5 and 72 h. After haemodilution 50% with Fluosol, the Vd alternated between values greater and less than control throughout the 72 h. Haemodilution 25 or 50% with saline had little influence on Vd.