Pharmacokinetics of tirilazad and U-89678, an active, reduced metabolite, following acute head trauma in adults.

Abstract

The pharmacokinetics of tirilazad and U-89678 (an active metabolite) were evaluated in 55 adults (48 males, 7 females) with moderate or severe head injury who received 10.0 mg/kg/day tirilazad mesylate for 5 days. Trough plasma samples were obtained daily; serial plasma samples were obtained over one dosing interval on day 5. Plasma tirilazad and U-89678 were quantified by HPLC. Sixty-two percent of the subjects received concomitant anticonvulsants, of which 91% received phenytoin. Plasma tirilazad and U-89678 concentrations in head-injured patients were similar to or lower than those observed in healthy volunteers. Sufficient data were available to calculate pharmacokinetic parameters for day 5 in 26 patients; 11 received no anticonvulsants. The AUC0-6 (are under the concentration-time curve at 0-6 h) for tirilazad mesylate on day 5 in patients receiving anticonvulsants (median = 4972 ng h/mL) differed significantly from that in patients not receiving anticonvulsants (median = 9704 ng h/mL) (p = 0.0051). Similarly, the AUC0-6 of U-89678 in patients receiving anticonvulsants (median = 561 ng h/mL) was significantly different from that in patients who were not (median = 2494 ng h/mL) (p = 0.0016). Comparison of pharmacokinetic data from patients not receiving anticonvulsants to historical data in healthy volunteers suggests that head injury has little effect on tirilazad pharmacokinetics within 5 days of injury. These results suggest that the major factor affecting tirilazad pharmacokinetics in head-injured patients is concomitant use of enzyme-inducing anticonvulsants.

• Authors: J C Fleishaker, R N Straw, C J Cross
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 86 Issue 4 Pg. 434-7 (Apr 1997) ISSN: 0022-3549 [Print] United States
• PMID: 9109044 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• Pregnatrienes
• U 89678
• tirilazad

Topics

• Adult
• Area Under Curve
• Craniocerebral Trauma (blood, drug therapy)
• Female
• Humans
• Male
• Neuroprotective Agents (pharmacokinetics, therapeutic use)
• Pregnatrienes (pharmacokinetics, therapeutic use)