Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat

Steven Laizure, L. K. Franklin, D. G. Kaiser, C. L. Williams, R. C. Stevens, P. L. Sanders, M. Miller

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Tirilazad mesylate (Freedox, Upjohn) is the first agent of a new class of compounds called lazaroids currently under clinical investigation for its potential beneficial effects following neurotrauma. Tirilazad's therapeutic effect is due to its ability to inhibit iron-dependent lipid peroxidation. This study was conducted in Sprague-Dawley rats to determine the basic pharmacokinetics and distribution of tirilazad into the brain, heart, and liver. Rats (N = 50) were killed in groups of five at 0, 10, 20, and 40 min, and at 1.5, 2, 3, 4, 6, and 8 hr after intravenous administration of 10 mg/kg of tirilazad mesylate. Tirilazad was assayed in plasma, heart, liver, and brain tissue by HPLC. Using the mean concentrations at each time point, pharmacokinetic parameters were estimated using standard noncompartmental techniques and statistical moment theory. Tirilazad was rapidly eliminated from the plasma with a half-life of 2.4 hr and clearance of 6.1 ml/min. The volume of distribution at steady-state was large, 4.8 liters/kg. The concentrations of tirilazad were highest in the liver and heart and lowest in the plasma and brain. Elimination from tissues paralleled elimination from plasma with half-lives of 1.9, 1.6, and 1.5 hr in the brain, heart, and liver, respectively. Tirilazad appears to be a highly extracted, hepatically eliminated drug, suggesting its clearance is dependent on liver blood flow, and alterations in plasma protein binding are unlikely to affect its clearance but may affect the fraction unbound.

Original languageEnglish (US)
Pages (from-to)951-954
Number of pages4
JournalDrug Metabolism and Disposition
Volume21
Issue number5
StatePublished - Jan 1 1993

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Liver
Brain
Pharmacokinetics
tirilazad
Therapeutic Uses
Protein Binding
Intravenous Administration
Lipid Peroxidation
Sprague Dawley Rats
Half-Life
Blood Proteins
Iron
High Pressure Liquid Chromatography
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Laizure, S., Franklin, L. K., Kaiser, D. G., Williams, C. L., Stevens, R. C., Sanders, P. L., & Miller, M. (1993). Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat. Drug Metabolism and Disposition, 21(5), 951-954.

Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat. / Laizure, Steven; Franklin, L. K.; Kaiser, D. G.; Williams, C. L.; Stevens, R. C.; Sanders, P. L.; Miller, M.

In: Drug Metabolism and Disposition, Vol. 21, No. 5, 01.01.1993, p. 951-954.

Research output: Contribution to journalArticle

Laizure, S, Franklin, LK, Kaiser, DG, Williams, CL, Stevens, RC, Sanders, PL & Miller, M 1993, 'Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat', Drug Metabolism and Disposition, vol. 21, no. 5, pp. 951-954.
Laizure S, Franklin LK, Kaiser DG, Williams CL, Stevens RC, Sanders PL et al. Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat. Drug Metabolism and Disposition. 1993 Jan 1;21(5):951-954.
Laizure, Steven ; Franklin, L. K. ; Kaiser, D. G. ; Williams, C. L. ; Stevens, R. C. ; Sanders, P. L. ; Miller, M. / Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat. In: Drug Metabolism and Disposition. 1993 ; Vol. 21, No. 5. pp. 951-954.
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