title: 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.affiliation: Clinical Pharmacokinetics, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Fleishaker
authors.forename: R N
authors.initials: RN
authors.lastname: Straw
authors.forename: C J
authors.initials: CJ
authors.lastname: Cross
mesh_terms: D000328:Adult; D019540:Area Under Curve; D006259:Craniocerebral Trauma / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011281:Pregnatrienes / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D011281:Pregnatrienes; C087053:U 89678; C053355:tirilazad