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Joseph C. Fleishaker - One of the best experts on this subject based on the ideXlab platform.
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biotransformation of tirilazad in human 2 effect of ketoconazole on tirilazad clearance and oral bioavailability
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Joseph C. Fleishaker, L K Pearson, Larry C Wienkers, Paul G Pearson, Gary PetersAbstract:The effect of ketoconazole, a CYP3A inhibitor, on the oral bioavailability of tirilazad Mesylate was assessed in 12 healthy subjects, who received the following treatments in a crossover design: a) 10 mg/kg tirilazad Mesylate solution orally on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily, b) 10 mg/kg tirilazad Mesylate solution orally, c) 2 mg/kg i.v. tirilazad Mesylate solution on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily and d) 2mg/kg i.v. tirilazad Mesylate solution. Plasma concentrations of tirilazad Mesylate and its active reduced metabolites (U-89678 and U-87999) were measured by high-performance liquid chromatography. Urinary ratios of 6 beta-hydroxycortisol to cortisol (6 beta-OHC/C) were measured as an index of hepatic CYP3A activity. Ketoconazole increased mean tirilazad Mesylate area under the curve (AUC) values by 67% and 309% for i.v. and oral administration, respectively. Mean AUC values for U-89678 were increased 472% and 720% by ketoconazole coadministration with i.v. and oral tirilazad, respectively, whereas increases of > 10-fold in mean U-87999 AUC values were observed. These differences were statistically significant. These results indicate that ketoconazole inhibits the metabolism of these three compounds, which suggests that all of the compounds are substrates for CYP3A. Urinary 6 beta-OHC/C ratios did not reflect this level of effect of ketoconazole on CYP3A; this probe may not be useful for assessing the effect of CYP3A inhibitors. The absolute bioavailability of oral tirilazad was 8.7 +/- 4.8%; ketoconazole increased the bioavailability to 20.9 +/- 6.5%. Ketoconazole increased tirilazad Mesylate bioavailability by decreasing the first-pass liver and gut wall metabolism of tirilazad Mesylate to similar degrees.
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Gender does not affect the degree of induction of tirilazad clearance by phenobarbital.
European journal of clinical pharmacology, 1996Co-Authors: Joseph C. Fleishaker, L K Pearson, G. R. PetersAbstract:Tirilazad Mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad Mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg.kg-1 tirilazed Mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad Mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad Mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC(zero)-6 for U-89678 after the last tirilazad Mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response.
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the effect of phenytoin on the pharmacokinetics of tirilazad Mesylate in healthy male volunteers
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two-way crossover study. In both periods, 1.5 mg/kg tirilazad Mesylate was administered (as 10-minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad Mesylate and U-89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration-time curve [AUC(0–6)] for tirilazad Mesylate was significantly lower (p = 0.0061) after phenytoin treatment (3029 ± 982 ng · hr/ml) than after tirilazad Mesylate alone (4647 ± 1562 ng · hr/ml). AUC(0–6) for U-89,678 after dose 21 was reduced from 1485 ± 1173 ng · hr/ml after tirilazad Mesylate alone to 195 ± 223 ng · hr/ml after phenytoin coadministration. U-89678 normally accumulates during multiple dosing, but mean U-89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad Mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad Mesylate metabolism; it may also induce the metabolism of U-89678 or shunt tirilazad Mesylate metabolism through other pathways. Clinical Pharmacology and Therapeutics (1994) 56, 389–397; doi:10.1038/clpt.1994.153
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lack of a pharmacokinetic pharmacodynamic interaction between nimodipine and tirilazad Mesylate in healthy volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
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Lack of a Pharmacokinetic/Pharmacodynamic Interaction Between Nimodipine and Tirilazad Mesylate in Healthy Volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
G. R. Peters - One of the best experts on this subject based on the ideXlab platform.
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Gender does not affect the degree of induction of tirilazad clearance by phenobarbital.
European journal of clinical pharmacology, 1996Co-Authors: Joseph C. Fleishaker, L K Pearson, G. R. PetersAbstract:Tirilazad Mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad Mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg.kg-1 tirilazed Mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad Mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad Mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC(zero)-6 for U-89678 after the last tirilazad Mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response.
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the effect of phenytoin on the pharmacokinetics of tirilazad Mesylate in healthy male volunteers
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two-way crossover study. In both periods, 1.5 mg/kg tirilazad Mesylate was administered (as 10-minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad Mesylate and U-89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration-time curve [AUC(0–6)] for tirilazad Mesylate was significantly lower (p = 0.0061) after phenytoin treatment (3029 ± 982 ng · hr/ml) than after tirilazad Mesylate alone (4647 ± 1562 ng · hr/ml). AUC(0–6) for U-89,678 after dose 21 was reduced from 1485 ± 1173 ng · hr/ml after tirilazad Mesylate alone to 195 ± 223 ng · hr/ml after phenytoin coadministration. U-89678 normally accumulates during multiple dosing, but mean U-89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad Mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad Mesylate metabolism; it may also induce the metabolism of U-89678 or shunt tirilazad Mesylate metabolism through other pathways. Clinical Pharmacology and Therapeutics (1994) 56, 389–397; doi:10.1038/clpt.1994.153
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lack of a pharmacokinetic pharmacodynamic interaction between nimodipine and tirilazad Mesylate in healthy volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
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Lack of a Pharmacokinetic/Pharmacodynamic Interaction Between Nimodipine and Tirilazad Mesylate in Healthy Volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
Gary Peters - One of the best experts on this subject based on the ideXlab platform.
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biotransformation of tirilazad in human 2 effect of ketoconazole on tirilazad clearance and oral bioavailability
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Joseph C. Fleishaker, L K Pearson, Larry C Wienkers, Paul G Pearson, Gary PetersAbstract:The effect of ketoconazole, a CYP3A inhibitor, on the oral bioavailability of tirilazad Mesylate was assessed in 12 healthy subjects, who received the following treatments in a crossover design: a) 10 mg/kg tirilazad Mesylate solution orally on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily, b) 10 mg/kg tirilazad Mesylate solution orally, c) 2 mg/kg i.v. tirilazad Mesylate solution on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily and d) 2mg/kg i.v. tirilazad Mesylate solution. Plasma concentrations of tirilazad Mesylate and its active reduced metabolites (U-89678 and U-87999) were measured by high-performance liquid chromatography. Urinary ratios of 6 beta-hydroxycortisol to cortisol (6 beta-OHC/C) were measured as an index of hepatic CYP3A activity. Ketoconazole increased mean tirilazad Mesylate area under the curve (AUC) values by 67% and 309% for i.v. and oral administration, respectively. Mean AUC values for U-89678 were increased 472% and 720% by ketoconazole coadministration with i.v. and oral tirilazad, respectively, whereas increases of > 10-fold in mean U-87999 AUC values were observed. These differences were statistically significant. These results indicate that ketoconazole inhibits the metabolism of these three compounds, which suggests that all of the compounds are substrates for CYP3A. Urinary 6 beta-OHC/C ratios did not reflect this level of effect of ketoconazole on CYP3A; this probe may not be useful for assessing the effect of CYP3A inhibitors. The absolute bioavailability of oral tirilazad was 8.7 +/- 4.8%; ketoconazole increased the bioavailability to 20.9 +/- 6.5%. Ketoconazole increased tirilazad Mesylate bioavailability by decreasing the first-pass liver and gut wall metabolism of tirilazad Mesylate to similar degrees.
Doriano Fabbro - One of the best experts on this subject based on the ideXlab platform.
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activation mutations of human c kit resistant to imatinib Mesylate are sensitive to the tyrosine kinase inhibitor pkc412
Blood, 2005Co-Authors: Joseph D Growney, Doriano Fabbro, Jennifer J Clark, Jennifer Adelsperger, Richard Stone, James D Griffin, Gary D GillilandAbstract:Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib Mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib Mesylate. In these cells, PKC412, but not imatinib Mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib Mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib Mesylate-resistant D816V or D816Y activation mutations.
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dual specific src and abl kinase inhibitors pp1 and cgp76030 inhibit growth and survival of cells expressing imatinib Mesylate resistant bcr abl kinases
Blood, 2003Co-Authors: Markus Warmuth, Elisabeth Buchdunger, Nicola Simon, Olga Mitina, Ruth Mathes, Doriano Fabbro, Paul W Manley, Karin Forster, Ismail Moarefi, Michael HallekAbstract:The leukemogenic tyrosine kinase Bcr-Abl contains a highly conserved inhibitor-binding pocket (IBP), which serves as a binding site for imatinib Mesylate. Mutations at the IBP may lead to resistance of the Abl kinase against imatinib Mesylate. To examine the mechanisms of imatinib Mesylate binding and resistance in more detail, we created several point mutations at amino acid positions 315 and 380 of Abl, blocking the access to the IBP and rendering Bcr-Abl imatinib Mesylate–resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (Asp276Ser/Glu279Ser) also led to imatinib Mesylate resistance, suggesting that the inhibitor required inactivation of the kinase prior to binding. These Bcr-Abl mutants were then used to evaluate the binding mode and specificity of 2 compounds, PP1 and CGP76030, originally characterized as Src kinase inhibitors. Both compounds inhibited Bcr-Abl in a concentration-dependent manner by overlapping binding modes. However, in contrast to imatinib Mesylate, PP1 and CGP76030 blocked cell growth and survival in cells expressing various inhibitor-resistant Abl mutants. Studies on the potential signaling mechanisms demonstrated that in cells expressing inhibitor-resistant Bcr-Abl mutants, PP1 and CGP76030 inhibited the activity of Src family tyrosine kinases and Akt but not signal transducer and activator of transcription–5 (STAT5) and JUN kinase (Jnk). The results suggest that the use of Src kinase inhibitors is a potential strategy to prevent or overcome clonal evolution of imatinib Mesylate resistance in Bcr-Abl+ leukemia.
Laura K Hulst - One of the best experts on this subject based on the ideXlab platform.
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the effect of phenytoin on the pharmacokinetics of tirilazad Mesylate in healthy male volunteers
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two-way crossover study. In both periods, 1.5 mg/kg tirilazad Mesylate was administered (as 10-minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad Mesylate and U-89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration-time curve [AUC(0–6)] for tirilazad Mesylate was significantly lower (p = 0.0061) after phenytoin treatment (3029 ± 982 ng · hr/ml) than after tirilazad Mesylate alone (4647 ± 1562 ng · hr/ml). AUC(0–6) for U-89,678 after dose 21 was reduced from 1485 ± 1173 ng · hr/ml after tirilazad Mesylate alone to 195 ± 223 ng · hr/ml after phenytoin coadministration. U-89678 normally accumulates during multiple dosing, but mean U-89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad Mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad Mesylate metabolism; it may also induce the metabolism of U-89678 or shunt tirilazad Mesylate metabolism through other pathways. Clinical Pharmacology and Therapeutics (1994) 56, 389–397; doi:10.1038/clpt.1994.153
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lack of a pharmacokinetic pharmacodynamic interaction between nimodipine and tirilazad Mesylate in healthy volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
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Lack of a Pharmacokinetic/Pharmacodynamic Interaction Between Nimodipine and Tirilazad Mesylate in Healthy Volunteers
The Journal of Clinical Pharmacology, 1994Co-Authors: Joseph C. Fleishaker, Laura K Hulst, G. R. PetersAbstract:The potential interaction between tirilazad Mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad Mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad Mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad Mesylate clearance (34.9 ± 8.96 L/hr) and half-life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad Mesylate and nimodipine is detectable after single-dose administration.
