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Peter K. Honig - One of the best experts on this subject based on the ideXlab platform.
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temporal decline in filling prescriptions for Terfenadine closely in time with those for either ketoconazole or erythromycin
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Greg A Burkhart, Michael J Sevka, Robert Temple, Peter K. HonigAbstract:Temporal changes in the rates of filling Terfenadine prescriptions within 2 days of those for either oral erythromycin or oral ketoconazole were described with use of paid pharmacy claims data from 1988 through 1994 in state Medicaid programs from Michigan and Ohio and in a large health maintenance organization. There were rapid and significant declines in the rates of filling prescriptions for either erythromycin or ketoconazole within 2 days of prescriptions for Terfenadine in all three databases that coincided with 1992 publicity about the cardiovascular risk of Terfenadine. These findings suggest that the use of Terfenadine with contraindicated medications has declined in response to relabeling and publicity concerning the safe use of Terfenadine. Further study is necessary to estimate the absolute level of concurrent use of Terfenadine with contraindicated medications.
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Grapefruit Juice Alters the Systemic Bioavailability and Cardiac Repolarization of Terfenadine in Poor Metabolizers of Terfenadine
Journal of clinical pharmacology, 1996Co-Authors: Peter K. Honig, Dale C. Wortham, Alexander Lazarev, Louis R. CantilenaAbstract:A prospective cohort study was conducted to examine the effects of double-strength grapefruit juice on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics of Terfenadine in poor metabolizers of Terfenadine. Six healthy volunteers who were previously found to be poor metabolizers of Terfenadine were studied, with each participant serving as his or her own control. In phase I of the study, Terfenadine was given to participants at recommended dosages until steady state was achieved (60 mg twice daily for 7 days). In phase II, participants began receiving concomitant twice-daily, double-strength servings of grapefruit juice for 7 days. Serial pharmacokinetic and pharmacodynamic determinations were made after each phase of the study. The main outcome measures were serum concentrations of Terfenadine and Terfenadine acid metabolite, and corrected QT intervals as determined by 12-lead electrocardiogram. Significant changes occurred in time to maximum concentration (tmax) and area under the concentration-time curve (AUC) of Terfenadine and Terfenadine acid metabolite after addition of grapefruit juice. All participants had detectable concentrations of unmetabolized Terfenadine at the end of Phase I, which were quantified in three of the six participants. Further, all participants had increased and quantifiable levels of unmetabolized Terfenadine after addition of grapefruit juice that were associated with prolongation of the QT interval relative to the baseline control period without Terfenadine. Grapefruit juice did not alter the elimination half-life (t1/2) of Terfenadine acid metabolite. Because of the intraindividual variability in the pharmacokinetics of Terfenadine, further study is needed to confirm these results.
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Grapefruit juice alters Terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram
Clinical pharmacology and therapeutics, 1996Co-Authors: Robert E. Benton, Kaveh Zamani, Peter K. Honig, Louis R. Cantilena, Raymond L WoosleyAbstract:Objectives To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of Terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of Terfenadine. Methods Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of Terfenadine and its acid metabolite Terfenadine carboxylate. All subjects received 60 mg Terfenadine twice a day with 240 ml water for 7 days. They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with Terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after Terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma Terfenadine and metabolite levels were measured on days 7 and 14. Results None of the 12 subjects had quantifiable levels of Terfenadine when the drug was administered with water. All six subjects who took Terfenadine and drank grapefruit juice simultaneously had quantifiable Terfenadine levels. Only two of six who drank grapefruit juice 2 hours after Terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delaye dgroup. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. Conclusions Administration of grapefruit juice concomitantly with Terfenadine may lead to an increase in systemic Terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear. Clinical Pharmacology & Therapeutics (1996) 59, 383–388; doi:
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Population variability in the pharmacokinetics of Terfenadine: the case for a pseudo-polymorphism with clinical implications.
Drug metabolism and drug interactions, 1994Co-Authors: Peter K. Honig, J.e. Smith, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is nearly completely first pass biotransformed. Unmetabolized Terfenadine plasma concentrations have been associated with altered cardiac repolarization. During previous drug interaction studies, 2 subjects were found to have quantifiable concentrations of unmetabolized Terfenadine with accompanying electrocardiographic repolarization changes while on Terfenadine alone. To determine whether these subjects were representative of the population, 150 healthy volunteers (109 males, 41 females, ages 19-49) were screened for their ability to metabolize Terfenadine after achieving steady-state. Blood was obtained at known times of maximum Terfenadine concentration after dosing. Eleven subjects had quantifiable concentrations of Terfenadine demonstrating wide intersubject variability in Terfenadine metabolism. Further studies to determine whether such subjects are more susceptible to untoward Terfenadine-associated events are underway.
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comparison of the effect of the macrolide antibiotics erythromycin clarithromycin and azithromycin on Terfenadine steady state pharmacokinetics and electrocardiographic parameters
Drug Investigation, 1994Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is a nonsedating histamine H1-antagonist that, when given with ketoconazole, results in accumulation of parent Terfenadine and altered cardiac repolarisation in susceptible individuals. This prospective cohort study, designed to assess macrolide effects on Terfenadine pharmacokinetics and electrocardiogram (ECG) parameters, evaluated 18 healthy male and female volunteers who received Terfenadine to steady-state. Equal numbers (6) were randomised to receive either erythromycin, clarithromycin or azithromycin at recommended doses while continuing Terfenadine. Macrolide monotherapy effects on the ECG were also investigated. Pharmacokinetic profiles for Terfenadine were performed before and after the addition of macrolide therapy, and ECGs were obtained at baseline and predose on days of blood sampling. Erythromycin and clarithromycin significantly affected the pharmacokinetics of Terfenadine. Three of 6 volunteers receiving erythromycin and 4 of 6 receiving clarithromycin demonstrated accumulation of quantifiable unmetabolised Terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on Terfenadine pharmacokinetics or cardiac pharmacodynamics.
Charles Nordin - One of the best experts on this subject based on the ideXlab platform.
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Terfenadine blocks time dependent ca2 na and k channels in guinea pig ventricular myocytes
Journal of Cardiovascular Pharmacology, 1995Co-Authors: Zhen Ming, Charles NordinAbstract:Terfenadine, which blocks delayed rectifier K+ channels (Ik), is structurally related to diphenylalkylamine L-type Ca2+ channel (ICa) blockers and has been reported to render Purkinje fibers inexcitable. We used standard whole-cell patch clamp techniques in isolated guinea pig ventricular myocytes to investigate the direct effect of Terfenadine on ICa after discovering that the upstrokes of early afterdepolarizations in guinea pig myocytes were inhibited by the drug at concentrations > or = 10(-6)M. Some data analyzing the effect of Terfenadine on time-dependent Na+ channels (INa) and IK also were obtained. All experiments were controlled for time of intracellular dialysis. Terfenadine (3 x 10(-6)M) reduced peak ICa (measured in either K+-containing or Cs+-substituted intracellular solutions from holding potentials of -40 mV) after 10 min exposure [peak at 0 mV in K+-deficient dialysis solution -4.2 +/- 2.3 pA/pF (mean +/- SD, n = 5) versus -13.02 +/- 4.33 pA/pF in control solution (n = 5), p < 0.01], and ICa was almost completely blocked after 15 min drug exposure. Ten minutes of exposure to Terfenadine (3 x 10-6M) also caused near-complete blockade of peak INa when INa was measured at -40 mV after 300 ms conditioning pulses from a holding potential of -40 to potentials between -60 and -90 mV. The effect was much less pronounced when INa was measured from a holding potential of -90 mV. After exposure to Terfenadine 3 x 10 (-6)M, IK density, measured as peak tail current at -40 mV after 300-ms depolarizations, was also reduced but not eliminated at membrane potentials between -20 and +60 mV. In contrast, exposure to Terfenadine caused no significant change in the current-voltage relationship after 300-ms steps from -90 to +60 mV. Terfenadine had no effect on time constants of decay of IK or ICa. These results suggest that Terfenadine blocks several time- and voltage-dependent channels, possibly by binding to a common protein structure, not related to ion selectivity, that is primarily associated with time-dependent activation of channel conductance.
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Terfenadine blocks time-dependent Ca2+, Na+, and K+ channels in guinea pig ventricular myocytes.
Journal of cardiovascular pharmacology, 1995Co-Authors: Zhen Ming, Charles NordinAbstract:Terfenadine, which blocks delayed rectifier K+ channels (Ik), is structurally related to diphenylalkylamine L-type Ca2+ channel (ICa) blockers and has been reported to render Purkinje fibers inexcitable. We used standard whole-cell patch clamp techniques in isolated guinea pig ventricular myocytes to investigate the direct effect of Terfenadine on ICa after discovering that the upstrokes of early afterdepolarizations in guinea pig myocytes were inhibited by the drug at concentrations > or = 10(-6)M. Some data analyzing the effect of Terfenadine on time-dependent Na+ channels (INa) and IK also were obtained. All experiments were controlled for time of intracellular dialysis. Terfenadine (3 x 10(-6)M) reduced peak ICa (measured in either K+-containing or Cs+-substituted intracellular solutions from holding potentials of -40 mV) after 10 min exposure [peak at 0 mV in K+-deficient dialysis solution -4.2 +/- 2.3 pA/pF (mean +/- SD, n = 5) versus -13.02 +/- 4.33 pA/pF in control solution (n = 5), p < 0.01], and ICa was almost completely blocked after 15 min drug exposure. Ten minutes of exposure to Terfenadine (3 x 10-6M) also caused near-complete blockade of peak INa when INa was measured at -40 mV after 300 ms conditioning pulses from a holding potential of -40 to potentials between -60 and -90 mV. The effect was much less pronounced when INa was measured from a holding potential of -90 mV. After exposure to Terfenadine 3 x 10 (-6)M, IK density, measured as peak tail current at -40 mV after 300-ms depolarizations, was also reduced but not eliminated at membrane potentials between -20 and +60 mV. In contrast, exposure to Terfenadine caused no significant change in the current-voltage relationship after 300-ms steps from -90 to +60 mV. Terfenadine had no effect on time constants of decay of IK or ICa. These results suggest that Terfenadine blocks several time- and voltage-dependent channels, possibly by binding to a common protein structure, not related to ion selectivity, that is primarily associated with time-dependent activation of channel conductance.
Louis R. Cantilena - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit Juice Alters the Systemic Bioavailability and Cardiac Repolarization of Terfenadine in Poor Metabolizers of Terfenadine
Journal of clinical pharmacology, 1996Co-Authors: Peter K. Honig, Dale C. Wortham, Alexander Lazarev, Louis R. CantilenaAbstract:A prospective cohort study was conducted to examine the effects of double-strength grapefruit juice on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics of Terfenadine in poor metabolizers of Terfenadine. Six healthy volunteers who were previously found to be poor metabolizers of Terfenadine were studied, with each participant serving as his or her own control. In phase I of the study, Terfenadine was given to participants at recommended dosages until steady state was achieved (60 mg twice daily for 7 days). In phase II, participants began receiving concomitant twice-daily, double-strength servings of grapefruit juice for 7 days. Serial pharmacokinetic and pharmacodynamic determinations were made after each phase of the study. The main outcome measures were serum concentrations of Terfenadine and Terfenadine acid metabolite, and corrected QT intervals as determined by 12-lead electrocardiogram. Significant changes occurred in time to maximum concentration (tmax) and area under the concentration-time curve (AUC) of Terfenadine and Terfenadine acid metabolite after addition of grapefruit juice. All participants had detectable concentrations of unmetabolized Terfenadine at the end of Phase I, which were quantified in three of the six participants. Further, all participants had increased and quantifiable levels of unmetabolized Terfenadine after addition of grapefruit juice that were associated with prolongation of the QT interval relative to the baseline control period without Terfenadine. Grapefruit juice did not alter the elimination half-life (t1/2) of Terfenadine acid metabolite. Because of the intraindividual variability in the pharmacokinetics of Terfenadine, further study is needed to confirm these results.
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Grapefruit juice alters Terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram
Clinical pharmacology and therapeutics, 1996Co-Authors: Robert E. Benton, Kaveh Zamani, Peter K. Honig, Louis R. Cantilena, Raymond L WoosleyAbstract:Objectives To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of Terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of Terfenadine. Methods Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of Terfenadine and its acid metabolite Terfenadine carboxylate. All subjects received 60 mg Terfenadine twice a day with 240 ml water for 7 days. They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with Terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after Terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma Terfenadine and metabolite levels were measured on days 7 and 14. Results None of the 12 subjects had quantifiable levels of Terfenadine when the drug was administered with water. All six subjects who took Terfenadine and drank grapefruit juice simultaneously had quantifiable Terfenadine levels. Only two of six who drank grapefruit juice 2 hours after Terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delaye dgroup. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. Conclusions Administration of grapefruit juice concomitantly with Terfenadine may lead to an increase in systemic Terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear. Clinical Pharmacology & Therapeutics (1996) 59, 383–388; doi:
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Population variability in the pharmacokinetics of Terfenadine: the case for a pseudo-polymorphism with clinical implications.
Drug metabolism and drug interactions, 1994Co-Authors: Peter K. Honig, J.e. Smith, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is nearly completely first pass biotransformed. Unmetabolized Terfenadine plasma concentrations have been associated with altered cardiac repolarization. During previous drug interaction studies, 2 subjects were found to have quantifiable concentrations of unmetabolized Terfenadine with accompanying electrocardiographic repolarization changes while on Terfenadine alone. To determine whether these subjects were representative of the population, 150 healthy volunteers (109 males, 41 females, ages 19-49) were screened for their ability to metabolize Terfenadine after achieving steady-state. Blood was obtained at known times of maximum Terfenadine concentration after dosing. Eleven subjects had quantifiable concentrations of Terfenadine demonstrating wide intersubject variability in Terfenadine metabolism. Further studies to determine whether such subjects are more susceptible to untoward Terfenadine-associated events are underway.
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comparison of the effect of the macrolide antibiotics erythromycin clarithromycin and azithromycin on Terfenadine steady state pharmacokinetics and electrocardiographic parameters
Drug Investigation, 1994Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is a nonsedating histamine H1-antagonist that, when given with ketoconazole, results in accumulation of parent Terfenadine and altered cardiac repolarisation in susceptible individuals. This prospective cohort study, designed to assess macrolide effects on Terfenadine pharmacokinetics and electrocardiogram (ECG) parameters, evaluated 18 healthy male and female volunteers who received Terfenadine to steady-state. Equal numbers (6) were randomised to receive either erythromycin, clarithromycin or azithromycin at recommended doses while continuing Terfenadine. Macrolide monotherapy effects on the ECG were also investigated. Pharmacokinetic profiles for Terfenadine were performed before and after the addition of macrolide therapy, and ECGs were obtained at baseline and predose on days of blood sampling. Erythromycin and clarithromycin significantly affected the pharmacokinetics of Terfenadine. Three of 6 volunteers receiving erythromycin and 4 of 6 receiving clarithromycin demonstrated accumulation of quantifiable unmetabolised Terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on Terfenadine pharmacokinetics or cardiac pharmacodynamics.
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Terfenadine-Ketoconazole Interaction: Pharmacokinetic and Electrocardiographic Consequences
JAMA, 1993Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, Dale P. Conner, James C Mullin, Louis R. CantilenaAbstract:Objective. —To examine prospectively the effects of ketoconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (corrected QT intervals) of Terfenadine in men and women. Design. —Prospective cohort study with each subject serving as his or her own control. Setting. —Outpatient cardiology clinic and inpatient telemetry unit for monitoring period. Participants. —Six healthy volunteers (four men and two women, aged 24 to 35 years) not taking any prescription or over-the-counter medications. Intervention. —After achieving a steady state while taking Terfenadine (60 mg every 12 hours for 7 days), daily concomitant oral ketoconazole (200 mg every 12 hours) was added to the subjects' regimen. Pharmacokinetic profiles were obtained while subjects were taking Terfenadine alone and after the addition of ketoconazole. Electrocardiograms were obtained at baseline, after 1 week of taking Terfenadine alone, and at the time of the second pharmacokinetic profile after the addition of ketoconazole to the regimen. Main Outcome Measures. —Terfenadine and its acid metabolite serum concentrations and corrected QT intervals. Results. —All subjects had detectable levels of unmetabolized Terfenadine after the addition of ketoconazole, which was associated with QT prolongation. Only two of the six subjects could complete the entire course of ketoconazole coadministration. Four subjects received a shortened duration of ketoconazole therapy because of significant electrocardiographic repolarization abnormalities. There was a significant change in the area under the curve of the acid metabolite of Terfenadine after the addition of ketoconazole administration. Conclusions. —Ketoconazole alters the metabolism of Terfenadine in normal men and women and results in the accumulation of unmetabolized parent drug, which is associated with significant prolongation of the corrected QT interval. This drug combination should be avoided. (JAMA. 1993;269:1513-1518)
Kaveh Zamani - One of the best experts on this subject based on the ideXlab platform.
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Grapefruit juice alters Terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram
Clinical pharmacology and therapeutics, 1996Co-Authors: Robert E. Benton, Kaveh Zamani, Peter K. Honig, Louis R. Cantilena, Raymond L WoosleyAbstract:Objectives To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of Terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of Terfenadine. Methods Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of Terfenadine and its acid metabolite Terfenadine carboxylate. All subjects received 60 mg Terfenadine twice a day with 240 ml water for 7 days. They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with Terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after Terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma Terfenadine and metabolite levels were measured on days 7 and 14. Results None of the 12 subjects had quantifiable levels of Terfenadine when the drug was administered with water. All six subjects who took Terfenadine and drank grapefruit juice simultaneously had quantifiable Terfenadine levels. Only two of six who drank grapefruit juice 2 hours after Terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delaye dgroup. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. Conclusions Administration of grapefruit juice concomitantly with Terfenadine may lead to an increase in systemic Terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear. Clinical Pharmacology & Therapeutics (1996) 59, 383–388; doi:
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Population variability in the pharmacokinetics of Terfenadine: the case for a pseudo-polymorphism with clinical implications.
Drug metabolism and drug interactions, 1994Co-Authors: Peter K. Honig, J.e. Smith, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is nearly completely first pass biotransformed. Unmetabolized Terfenadine plasma concentrations have been associated with altered cardiac repolarization. During previous drug interaction studies, 2 subjects were found to have quantifiable concentrations of unmetabolized Terfenadine with accompanying electrocardiographic repolarization changes while on Terfenadine alone. To determine whether these subjects were representative of the population, 150 healthy volunteers (109 males, 41 females, ages 19-49) were screened for their ability to metabolize Terfenadine after achieving steady-state. Blood was obtained at known times of maximum Terfenadine concentration after dosing. Eleven subjects had quantifiable concentrations of Terfenadine demonstrating wide intersubject variability in Terfenadine metabolism. Further studies to determine whether such subjects are more susceptible to untoward Terfenadine-associated events are underway.
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comparison of the effect of the macrolide antibiotics erythromycin clarithromycin and azithromycin on Terfenadine steady state pharmacokinetics and electrocardiographic parameters
Drug Investigation, 1994Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, Louis R. CantilenaAbstract:Terfenadine is a nonsedating histamine H1-antagonist that, when given with ketoconazole, results in accumulation of parent Terfenadine and altered cardiac repolarisation in susceptible individuals. This prospective cohort study, designed to assess macrolide effects on Terfenadine pharmacokinetics and electrocardiogram (ECG) parameters, evaluated 18 healthy male and female volunteers who received Terfenadine to steady-state. Equal numbers (6) were randomised to receive either erythromycin, clarithromycin or azithromycin at recommended doses while continuing Terfenadine. Macrolide monotherapy effects on the ECG were also investigated. Pharmacokinetic profiles for Terfenadine were performed before and after the addition of macrolide therapy, and ECGs were obtained at baseline and predose on days of blood sampling. Erythromycin and clarithromycin significantly affected the pharmacokinetics of Terfenadine. Three of 6 volunteers receiving erythromycin and 4 of 6 receiving clarithromycin demonstrated accumulation of quantifiable unmetabolised Terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on Terfenadine pharmacokinetics or cardiac pharmacodynamics.
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the effect of fluconazole on the steady state pharmacokinetics and electrocardiographic pharmacodynamics of Terfenadine in humans
Clinical Pharmacology & Therapeutics, 1993Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, James C MullinAbstract:Terfenadine is rapidly and nearly completely biotransformed during a first pass to an active acid metabolite. Accumulation of unmetabolized Terfenadine has been associated with altered cardiac repolarization. Drug-drug interactions resulting in the accumulation of Terfenadine have been reported for ketoconazole and erythromycin. Six subjects were given the recommended dose of Terfenadine (60 mg every 12 hours) for 7 days before initiation of oral fluconazole (200 mg once daily). The mean metabolite area under the concentration-time curve increased by 34% and the time to maximum concentration of the metabolite was delayed from 2.3 to 4 hours by concurrent fluconazole. Unmetabolized Terfenadine was not present in any subject, and cardiac repolarization was not significantly changed from baseline during any phase of the study. We conclude that a pharmacokinetic interaction between Terfenadine and fluconazole exists; however, the absence of accumulation of parent Terfenadine in plasma suggests that a clinically significant interaction is unlikely. Clinical Pharmacology and Therapeutics (1993) 53, 630–636; doi:10.1038/clpt.1993.83
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Terfenadine-Ketoconazole Interaction: Pharmacokinetic and Electrocardiographic Consequences
JAMA, 1993Co-Authors: Peter K. Honig, Dale C. Wortham, Kaveh Zamani, Dale P. Conner, James C Mullin, Louis R. CantilenaAbstract:Objective. —To examine prospectively the effects of ketoconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (corrected QT intervals) of Terfenadine in men and women. Design. —Prospective cohort study with each subject serving as his or her own control. Setting. —Outpatient cardiology clinic and inpatient telemetry unit for monitoring period. Participants. —Six healthy volunteers (four men and two women, aged 24 to 35 years) not taking any prescription or over-the-counter medications. Intervention. —After achieving a steady state while taking Terfenadine (60 mg every 12 hours for 7 days), daily concomitant oral ketoconazole (200 mg every 12 hours) was added to the subjects' regimen. Pharmacokinetic profiles were obtained while subjects were taking Terfenadine alone and after the addition of ketoconazole. Electrocardiograms were obtained at baseline, after 1 week of taking Terfenadine alone, and at the time of the second pharmacokinetic profile after the addition of ketoconazole to the regimen. Main Outcome Measures. —Terfenadine and its acid metabolite serum concentrations and corrected QT intervals. Results. —All subjects had detectable levels of unmetabolized Terfenadine after the addition of ketoconazole, which was associated with QT prolongation. Only two of the six subjects could complete the entire course of ketoconazole coadministration. Four subjects received a shortened duration of ketoconazole therapy because of significant electrocardiographic repolarization abnormalities. There was a significant change in the area under the curve of the acid metabolite of Terfenadine after the addition of ketoconazole administration. Conclusions. —Ketoconazole alters the metabolism of Terfenadine in normal men and women and results in the accumulation of unmetabolized parent drug, which is associated with significant prolongation of the corrected QT interval. This drug combination should be avoided. (JAMA. 1993;269:1513-1518)
Daniel Eikel - One of the best experts on this subject based on the ideXlab platform.
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liquid extraction surface analysis mass spectrometry lesa ms as a novel profiling tool for drug distribution and metabolism analysis the Terfenadine example
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Daniel Eikel, Marissa Vavrek, Sheri Smith, Carol Aso, Suzie Yeh, Walte A Korfmache, Jack HenioAbstract:Liquid extraction surface analysis mass spectrometry (LESA-MS) is a novel surface profiling technique that combines micro-liquid extraction from a solid surface with nano-electrospray mass spectrometry. One potential application is the examination of the distribution of drugs and their metabolites by analyzing ex vivo tissue sections, an area where quantitative whole body autoradiography (QWBA) is traditionally employed. However, QWBA relies on the use of radiolabeled drugs and is limited to total radioactivity measured whereas LESA-MS can provide drug- and metabolite-specific distribution information. Here, we evaluate LESA-MS, examining the distribution and biotransformation of unlabeled Terfenadine in mice and compare our findings to QWBA, whole tissue LC/MS/MS and MALDI-MSI. The spatial resolution of LESA-MS can be optimized to ca. 1 mm on tissues such as brain, liver and kidney, also enabling drug profiling within a single organ. LESA-MS can readily identify the biotransformation of Terfenadine to its major, active metabolite fexofenadine. Relative quantification can confirm the rapid absorption of terfendine after oral dosage, its extensive first pass metabolism and the distribution of both compounds into systemic tissues such as muscle, spleen and kidney. The elimination appears to be consistent with biliary excretion and only trace levels of fexofenadine could be confirmed in brain. We found LESA-MS to be more informative in terms of drug distribution than a comparable MALDI-MS imaging study, likely due to its favorable overall sensitivity due to the larger surface area sampled. LESA-MS appears to be a useful new profiling tool for examining the distribution of drugs and their metabolites in tissue sections. Copyright © 2011 John Wiley & Sons, Ltd.
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liquid extraction surface analysis mass spectrometry lesa ms as a novel profiling tool for drug distribution and metabolism analysis the Terfenadine example
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Daniel Eikel, Marissa Vavrek, Sheri Smith, Suzie Yeh, Carol Bason, Walter A Korfmacher, Jack HenionAbstract:Liquid extraction surface analysis mass spectrometry (LESA-MS) is a novel surface profiling technique that combines micro-liquid extraction from a solid surface with nano-electrospray mass spectrometry. One potential application is the examination of the distribution of drugs and their metabolites by analyzing ex vivo tissue sections, an area where quantitative whole body autoradiography (QWBA) is traditionally employed. However, QWBA relies on the use of radiolabeled drugs and is limited to total radioactivity measured whereas LESA-MS can provide drug- and metabolite-specific distribution information. Here, we evaluate LESA-MS, examining the distribution and biotransformation of unlabeled Terfenadine in mice and compare our findings to QWBA, whole tissue LC/MS/MS and MALDI-MSI. The spatial resolution of LESA-MS can be optimized to ca. 1 mm on tissues such as brain, liver and kidney, also enabling drug profiling within a single organ. LESA-MS can readily identify the biotransformation of Terfenadine to its major, active metabolite fexofenadine. Relative quantification can confirm the rapid absorption of terfendine after oral dosage, its extensive first pass metabolism and the distribution of both compounds into systemic tissues such as muscle, spleen and kidney. The elimination appears to be consistent with biliary excretion and only trace levels of fexofenadine could be confirmed in brain. We found LESA-MS to be more informative in terms of drug distribution than a comparable MALDI-MS imaging study, likely due to its favorable overall sensitivity due to the larger surface area sampled. LESA-MS appears to be a useful new profiling tool for examining the distribution of drugs and their metabolites in tissue sections.
