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Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin Tizanidine and midazolam probes of cyp2c9 cyp1a2 and cyp3a4
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract:Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, Tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg Tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.
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rofecoxib is a potent inhibitor of cytochrome p450 1a2 studies with Tizanidine and caffeine in healthy subjects
British Journal of Clinical Pharmacology, 2006Co-Authors: Janne T Backman, Mikko Neuvonen, Jouko Laitila, Marjo J Karjalainen, Pertti J. NeuvonenAbstract:Aims Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate Tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. Methods In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg Tizanidine. Plasma concentrations and the urinary excretion of Tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. Results Rofecoxib increased the area under the plasma concentration–time curve (AUC0–∞) of Tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of Tizanidine (P < 0.05). Rofecoxib increased several fold the Tizanidine/M-3 and Tizanidine/M-4 ratios in plasma and urine and the Tizanidine/M-5, Tizanidine/M-9 and Tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the Tizanidine/metabolite ratios. Finally, the AUC0−25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). Conclusions Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of Tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.
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oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of Tizanidine by inhibiting cytochrome p450 1a2
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Marika T Granfors, Janne T Backman, Jouko Laitila, Pertti J. NeuvonenAbstract:Background and objective: Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with Tizanidine. Methods: In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg Tizanidine. Plasma and urine concentrations of Tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. Results: The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of Tizanidine was 3.9 times greater (P<.001) and the mean peak plasma Tizanidine concentration (Cmax) was 3.0 times higher (P<.001) in the OC users than in the control subjects. In 1 OC user the AUC0-infinity of Tizanidine exceeded the mean AUC0-infinity of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of Tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged Tizanidine into urine was, on average, 3.8 times greater (P=.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P<.001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC0-infinity and peak concentration of Tizanidine in plasma, with its excretion into urine, and with, for example, the Tizanidine/M-3 and Tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by Tizanidine more in the OC users (-29+/- 10 mm Hg and -21+/- 8 mm Hg, respectively) than in the control subjects (-17+/- 9 mm Hg and -13+/- 5 mm Hg, respectively) (P < .01). Conclusions: OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of Tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when Tizanidine is prescribed to OC users.
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oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of Tizanidine by inhibiting cytochrome p450 1a2
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Marika T Granfors, Janne T Backman, Jouko Laitila, Pertti J. NeuvonenAbstract:Background and objective Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with Tizanidine. Methods In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg Tizanidine. Plasma and urine concentrations of Tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. Results The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of Tizanidine was 3.9 times greater (P Conclusions OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of Tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when Tizanidine is prescribed to OC users.
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ciprofloxacin greatly increases concentrations and cypotensive effect of Tizanidine by inhibiting its cytochrome p450 1a2 mediated presystemic metabolism
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Marika T Granfors, Janne T Backman, Mikko Neuvonen, Pertti J. NeuvonenAbstract:Background and objective Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with Tizanidine. Methods In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg Tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of Tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. Results Ciprofloxacin increased the area under the plasma concentration–time curve from time 0 to infinity [AUC(0-∞)] of Tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of Tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (−35 mm Hg versus −15 mm Hg, P = .001), diastolic blood pressure (−24 mm Hg versus −11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC(0-∞) of Tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. Conclusions Ciprofloxacin greatly elevates plasma concentrations of Tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before Tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when Tizanidine is used concomitantly with ciprofloxacin. Clinical Pharmacology & Therapeutics (2004) 76, 598–606; doi: 10.1016/j.clpt.2004.08.018
Mehdi M Mirbagheri - One of the best experts on this subject based on the ideXlab platform.
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quantification of the effects of an alpha 2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique
Journal of Neuroengineering and Rehabilitation, 2010Co-Authors: Mehdi M Mirbagheri, David Chen, Wzev RymerAbstract:Background Despite numerous investigations, the impact of Tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of Tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of Tizanidine on ankle muscle intrinsic and reflex components.
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Quantification of the effects of an alpha-2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique
Journal of NeuroEngineering and Rehabilitation, 2010Co-Authors: Mehdi M Mirbagheri, David Chen, William Z. RymerAbstract:BACKGROUND: Despite numerous investigations, the impact of Tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of Tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of Tizanidine on ankle muscle intrinsic and reflex components.\n\nMETHODS: A series of perturbations was applied to the spastic ankle joint of twenty-one spinal cord injured subjects, and the resulting torques were recorded. A parallel-cascade system identification method was used to separate intrinsic and reflex torques, and to identify the contribution of these components to dynamic ankle stiffness at different ankle positions, while subjects remained relaxed.\n\nRESULTS: Following administration of a single oral dose of Tizanidine, stretch evoked joint torque at the ankle decreased significantly (p < 0.001) The peak-torque was reduced between 15% and 60% among the spinal cord injured subjects, and the average reduction was 25%. Using systems identification techniques, we found that this reduced torque could be attributed largely to a reduced reflex response, without measurable change in the muscle contribution. Reflex stiffness decreased significantly across a range of joint angles (p < 0.001) after using Tizanidine. In contrast, there were no significant changes in intrinsic muscle stiffness after the administration of Tizanidine.\n\nCONCLUSIONS: Our findings demonstrate that Tizanidine acts to reduce reflex mechanical responses substantially, without inducing comparable changes in intrinsic muscle properties in individuals with spinal cord injury. Thus, the pre-post difference in joint mechanical properties can be attributed to reflex changes alone. From a practical standpoint, use of a single "test" dose of Tizanidine may help clinicians decide whether the drug can helpful in controlling symptoms in particular subjects.
Wzev Rymer - One of the best experts on this subject based on the ideXlab platform.
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quantification of the effects of an alpha 2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique
Journal of Neuroengineering and Rehabilitation, 2010Co-Authors: Mehdi M Mirbagheri, David Chen, Wzev RymerAbstract:Background Despite numerous investigations, the impact of Tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of Tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of Tizanidine on ankle muscle intrinsic and reflex components.
David Chen - One of the best experts on this subject based on the ideXlab platform.
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quantification of the effects of an alpha 2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique
Journal of Neuroengineering and Rehabilitation, 2010Co-Authors: Mehdi M Mirbagheri, David Chen, Wzev RymerAbstract:Background Despite numerous investigations, the impact of Tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of Tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of Tizanidine on ankle muscle intrinsic and reflex components.
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Quantification of the effects of an alpha-2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique
Journal of NeuroEngineering and Rehabilitation, 2010Co-Authors: Mehdi M Mirbagheri, David Chen, William Z. RymerAbstract:BACKGROUND: Despite numerous investigations, the impact of Tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of Tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of Tizanidine on ankle muscle intrinsic and reflex components.\n\nMETHODS: A series of perturbations was applied to the spastic ankle joint of twenty-one spinal cord injured subjects, and the resulting torques were recorded. A parallel-cascade system identification method was used to separate intrinsic and reflex torques, and to identify the contribution of these components to dynamic ankle stiffness at different ankle positions, while subjects remained relaxed.\n\nRESULTS: Following administration of a single oral dose of Tizanidine, stretch evoked joint torque at the ankle decreased significantly (p < 0.001) The peak-torque was reduced between 15% and 60% among the spinal cord injured subjects, and the average reduction was 25%. Using systems identification techniques, we found that this reduced torque could be attributed largely to a reduced reflex response, without measurable change in the muscle contribution. Reflex stiffness decreased significantly across a range of joint angles (p < 0.001) after using Tizanidine. In contrast, there were no significant changes in intrinsic muscle stiffness after the administration of Tizanidine.\n\nCONCLUSIONS: Our findings demonstrate that Tizanidine acts to reduce reflex mechanical responses substantially, without inducing comparable changes in intrinsic muscle properties in individuals with spinal cord injury. Thus, the pre-post difference in joint mechanical properties can be attributed to reflex changes alone. From a practical standpoint, use of a single "test" dose of Tizanidine may help clinicians decide whether the drug can helpful in controlling symptoms in particular subjects.
Janne T Backman - One of the best experts on this subject based on the ideXlab platform.
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effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin Tizanidine and midazolam probes of cyp2c9 cyp1a2 and cyp3a4
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Jari J Lilja, Janne T Backman, Pertti J. NeuvonenAbstract:Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, Tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg Tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.
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rofecoxib is a potent inhibitor of cytochrome p450 1a2 studies with Tizanidine and caffeine in healthy subjects
British Journal of Clinical Pharmacology, 2006Co-Authors: Janne T Backman, Mikko Neuvonen, Jouko Laitila, Marjo J Karjalainen, Pertti J. NeuvonenAbstract:Aims Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate Tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. Methods In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg Tizanidine. Plasma concentrations and the urinary excretion of Tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. Results Rofecoxib increased the area under the plasma concentration–time curve (AUC0–∞) of Tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of Tizanidine (P < 0.05). Rofecoxib increased several fold the Tizanidine/M-3 and Tizanidine/M-4 ratios in plasma and urine and the Tizanidine/M-5, Tizanidine/M-9 and Tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the Tizanidine/metabolite ratios. Finally, the AUC0−25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). Conclusions Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of Tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.
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oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of Tizanidine by inhibiting cytochrome p450 1a2
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Marika T Granfors, Janne T Backman, Jouko Laitila, Pertti J. NeuvonenAbstract:Background and objective: Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with Tizanidine. Methods: In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg Tizanidine. Plasma and urine concentrations of Tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. Results: The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of Tizanidine was 3.9 times greater (P<.001) and the mean peak plasma Tizanidine concentration (Cmax) was 3.0 times higher (P<.001) in the OC users than in the control subjects. In 1 OC user the AUC0-infinity of Tizanidine exceeded the mean AUC0-infinity of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of Tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged Tizanidine into urine was, on average, 3.8 times greater (P=.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P<.001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC0-infinity and peak concentration of Tizanidine in plasma, with its excretion into urine, and with, for example, the Tizanidine/M-3 and Tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by Tizanidine more in the OC users (-29+/- 10 mm Hg and -21+/- 8 mm Hg, respectively) than in the control subjects (-17+/- 9 mm Hg and -13+/- 5 mm Hg, respectively) (P < .01). Conclusions: OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of Tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when Tizanidine is prescribed to OC users.
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oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of Tizanidine by inhibiting cytochrome p450 1a2
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Marika T Granfors, Janne T Backman, Jouko Laitila, Pertti J. NeuvonenAbstract:Background and objective Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with Tizanidine. Methods In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg Tizanidine. Plasma and urine concentrations of Tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. Results The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of Tizanidine was 3.9 times greater (P Conclusions OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of Tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when Tizanidine is prescribed to OC users.
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ciprofloxacin greatly increases concentrations and cypotensive effect of Tizanidine by inhibiting its cytochrome p450 1a2 mediated presystemic metabolism
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Marika T Granfors, Janne T Backman, Mikko Neuvonen, Pertti J. NeuvonenAbstract:Background and objective Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with Tizanidine. Methods In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg Tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of Tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. Results Ciprofloxacin increased the area under the plasma concentration–time curve from time 0 to infinity [AUC(0-∞)] of Tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of Tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (−35 mm Hg versus −15 mm Hg, P = .001), diastolic blood pressure (−24 mm Hg versus −11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC(0-∞) of Tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. Conclusions Ciprofloxacin greatly elevates plasma concentrations of Tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before Tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when Tizanidine is used concomitantly with ciprofloxacin. Clinical Pharmacology & Therapeutics (2004) 76, 598–606; doi: 10.1016/j.clpt.2004.08.018
