Perfluorochemical emulsions have been used in animals and man as a blood substitute. The emulsions are miscible with blood and thereby result in a vascular fluid which has different physiologic properties than normal blood. Patients receiving perfluorochemical emulsion transfusions will undoubtly be receiving other drugs. It is expected that the disposition of these comcomitantly administered drugs will be altered in such patients. Pharmacokinetic quantitation of these changes is necessary if dosing regimen adjustments are to be made in these patients to ensure the drug's efficacy. The research is designed to quantitate changes in pharmacokinetic parameters of select drugs in rats whose blood has been partially or completely exchanged with a commercially available perfluorochemical emulsion. The pharmacokinetics of the select drugs' metabolite(s) will simultaneously be determined to provide additional insight into which physiologic processes are being influenced by the perfluorochemical emulsion. An additional application of the information is to establish the potential utility of perfluorochemical emulsion transfusions as a technique for treating accidental or deliberate drug overdose or poisoning. The model drugs selected represent a particular pharmacokinetic behavior or are marker drugs to evaluate the functioning of a particular physiologic process. Their distribution, metabolism, and excretion will be studied in male, albino rats which first receive the drug alone, then undergo an exchange transfusion with a commercially available perfluorochemical emulsion and then are rechallenged repeatedly with the drug for several days after the exchange transfusion. The pharmacokinetic behavior/physiologic process and the select drugs to be investigated are; 1) low intrinsic hepatic clearance with no protein binding and hepatic metabolism (antipyrine); 2) high intrinsic hepatic clearance and hepatic blood flow (propranolol); 3) saturation (non-linear) pharmacokinetics (phenytoin); 4) complete renal excretion and glomerular filtration rate (gentamicin/ampicillin); 5) plasma esterase clearance (carbaryl); and 6) extensive tissue distribution and potential drug overdose treatment (desipramine). The pharmacokinetic parameter of both the select drug and its metabolite(s) will be determined from serum concentration and urinary excretion data. Assay methodology will be by high pressure liquid chromatography using literature techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033227-03
Application #
3344856
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Shrewsbury, R P; Hong, D D; White, L G et al. (1992) The effect of moderate haemodilution with Fluosol-DA or Hespan on the nonmicrosomal acetylation of sulphadimidine in the rat. J Pharm Pharmacol 44:84-8
Shrewsbury, R P (1991) Plasma volumes, blood volumes, and plasma protein concentrations after moderate haemodilution with fluosol-DA or normal saline in the rat. J Pharm Pharmacol 43:371-4
Shrewsbury, R P; White, L G (1990) The effect of moderate hemodilution with fluosol-DA or normal saline on acetaminophen disposition in the rat. Experientia 46:213-7
Shrewsbury, R P; Oliver, S R; White, L G (1989) The effect of moderately severe hemodilution with Fluosol-DA on cytochrome P-450 mediated antipyrine metabolism. Biomater Artif Cells Artif Organs 17:393-402
Shrewsbury, R P; Oliver, S R; Lewis, L M et al. (1989) The effect of varying extents of Fluosol-DA or normal saline haemodilution on the dose dependent kinetics of phenytoin in the rat. J Pharm Pharmacol 41:582-4
Shrewsbury, R P; White, L G (1989) The effect of moderate fluosol-DA hemodilution on gender specific metabolism of antipyrine. Res Commun Chem Pathol Pharmacol 64:455-62
Shrewsbury, R P; Oliver, S R; Anderson, W T et al. (1988) The effect of varying percentages of haemodilution with fluosol-DA or normal saline on antipyrine metabolism in the rat. J Pharm Pharmacol 40:392-8
Shrewsbury, R P; White, L G (1988) Some insights into the variations in antipyrine pharmacokinetics in the rat. Res Commun Chem Pathol Pharmacol 62:137-40
Shrewsbury, R P; Lewis, L M; Oliver, S R et al. (1987) Effect of moderate haemodilution with Fluosol-DA or normal saline on indocyanine green and (+)-propranolol kinetics. J Pharm Pharmacol 39:592-8
Shrewsbury, R P; Lewis, L M; Oliver, S R (1987) Effect of moderate haemodilution with Fluosol-DA or normal saline on low-dose phenytoin and (+/-)-5-(4-hydroxyphenyl)-5-phenylhydantoin kinetics. J Pharm Pharmacol 39:349-56

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