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1.
Pharmacology ; 86(5-6): 297-305, 2010.
Article in English | MEDLINE | ID: mdl-21071997

ABSTRACT

Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹4C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹4C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹4C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-ß-glucuronide, were identified.


Subject(s)
Fluorobenzenes/pharmacokinetics , Sodium Channel Blockers/pharmacokinetics , Administration, Oral , Adult , Half-Life , Humans , Kidney/metabolism , Male , Time Factors , Young Adult
2.
Aliment Pharmacol Ther ; 16(11): 1877-88, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12390096

ABSTRACT

BACKGROUND: Irritable bowel syndrome is a common functional gastrointestinal disorder which affects up to 20% of the population, with a predominance in females. AIM: To evaluate the efficacy and safety of tegaserod in female patients with irritable bowel syndrome characterized by symptoms of abdominal pain/discomfort and constipation. METHODS: In a randomized, double-blind, multicentre study, 1519 women received either tegaserod, 6 mg b.d. (n = 767), or placebo (n = 752) for 12 weeks, preceded by a 4-week baseline period without treatment and followed by a 4-week open withdrawal period. The primary efficacy evaluation was the patient's symptomatic response as measured by the Subject's Global Assessment of Relief. Other efficacy variables included abdominal pain/discomfort, bowel habits and bloating. RESULTS: Tegaserod produced significant (P < 0.05) improvements in the Subject's Global Assessment of Relief and other efficacy variables. These improvements were seen within the first week, and were maintained throughout the treatment period. After withdrawal of treatment, the symptoms rapidly returned. Overall, tegaserod was well tolerated. Diarrhoea was the most frequent adverse event; however, this led to discontinuation in only 1.6% of tegaserod-treated patients. CONCLUSIONS: Tegaserod, 6 mg b.d., produced rapid and sustained improvement of symptoms in female irritable bowel syndrome patients and was well tolerated.


Subject(s)
Colonic Diseases, Functional/drug therapy , Constipation/drug therapy , Gastrointestinal Agents/therapeutic use , Indoles/therapeutic use , Serotonin Receptor Agonists/therapeutic use , Adult , Colonic Diseases, Functional/complications , Constipation/etiology , Double-Blind Method , Female , Gastrointestinal Agents/adverse effects , Humans , Indoles/adverse effects , Middle Aged , Patient Satisfaction , Prospective Studies , Serotonin Receptor Agonists/adverse effects , Treatment Outcome
3.
Int J Clin Pharmacol Ther ; 39(6): 271-6, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11430636

ABSTRACT

OBJECTIVES: Imipramine is a tricyclic antidepressant drug with a considerable hepatic first-pass metabolism resulting in highly variable pharmacokinetic characteristics and desipramine as active major metabolite. This study describes the bioavailability of 3 formulations of imipramine. METHODS: In a randomized, three-period crossover study, 18 healthy male Caucasian subjects received single oral doses of Tofranil 25, Tofranil mite (10 mg) and an aqueous solution containing 25 mg imipramine-HCl. Serum concentrations of imipramine-HCl and its main metabolite desipramine were measured. The pharmacokinetic characteristics, Cmax, AUC, t1/2 and tmax were determined and the relative bioavailability of the two coated tablet formulations was calculated with the aqueous solution as reference. Safety and tolerability were assessed using vital signs, ECG, clinical laboratory and adverse event recording. RESULTS: The relative bioavailabilities of Tofranil 25 and Tofranil mite were 97% and 81%, respectively. The study medication was well tolerated. CONCLUSIONS: A sufficiently high extent of absorption was found for the test formulations ensuring therapeutic efficacy.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacokinetics , Imipramine/pharmacokinetics , Administration, Oral , Adult , Antidepressive Agents, Tricyclic/administration & dosage , Area Under Curve , Cross-Over Studies , Desipramine/pharmacokinetics , Half-Life , Humans , Imipramine/administration & dosage , Male , Tablets
4.
Fortschr Neurol Psychiatr ; 69(2): 86-9, 2001 Feb.
Article in German | MEDLINE | ID: mdl-11253562

ABSTRACT

In a randomised double blind parallel-group study in three centers budipine, a diphenylpiperidin derivate, was compared to amantadine with respect to efficacy and safety in the monotherapy of mild to moderate Parkinson's disease (PD). From 53 patients of either sex 27 patients were randomised to 3 x 20 mg/d budipine and 26 patients to 3 x 100 mg/d amantadine. The duration of treatment was 4 weeks in 1 center (21 patients) and 12 weeks in the other 2 centers (32 patients). Safety was measured by vital signs, ECG, adverse event recording and clinical laboratory. Both drugs caused a clinically relevant and statistically significant (p < 0.001) improvement of Parkinsonian symptoms according to the Webster-Rating-Scale (WRS) as compared to pretreatment values. With respect to the total WRS score sum there was no difference between the groups (p > 0.05; n.s.), while budipine showed a significantly (p < 0.05) better effect on the main symptom tremor after 12 weeks. During amantadine treatment more adverse events were observed than after budipine intake. Two patients left the study prematurely, one in the amantadine group due to psychiatric adverse events and one in the budipine group because of insufficient efficacy.


Subject(s)
Amantadine/therapeutic use , Antiparkinson Agents/therapeutic use , Parkinson Disease/drug therapy , Piperidines/therapeutic use , Aged , Aged, 80 and over , Amantadine/adverse effects , Antiparkinson Agents/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Piperidines/adverse effects
5.
Int J Clin Pharmacol Ther ; 37(4): 159-64, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10235417

ABSTRACT

OBJECTIVE: This drug-drug interaction study investigated the potential influence of the proton pump inhibitor pantoprazole on the CYP1A2 activity as assessed by urinary excretion of caffeine metabolites. SUBJECTS, MATERIALS AND METHODS: 12 healthy, non-smoking volunteers underwent two treatment periods of 7 days each in randomized order with once-daily oral intake of 40 mg pantoprazole (test) or placebo (reference). On days 6 and 7 of both periods, 200 mg caffeine was administered two hours after pantoprazole intake, i.e. at the expected t(max) of pantoprazole serum concentrations. Urinary excretion of the caffeine metabolites 1X, 1U, AFMU, 17U was measured up to 8 hours after caffeine intake. In accordance with recent guidelines on drug-drug interactions, lack of interaction was handled as an equivalence problem. RESULTS: Point estimate and 90% confidence intervals (CI) of the respective ratios test/reference were 0.91 (0.81, 1.03) for (1X + 1U + AFMU)/17U, indicative for CYP1A2 activity, 1.03 (0.94, 1.13) for AFMU/1X (N-acetyl transferase activity) and 1.01 (0.94, 1.09) for 1U/1X (xanthine oxidase activity). CONCLUSION: Pantoprazole does not induce CYP1A2 activity, consistent with previous findings following theophylline administration, nor does it have any influence on N-acetyl-transferase or xanthine oxidase activity.


Subject(s)
Benzimidazoles/pharmacology , Caffeine/metabolism , Central Nervous System Stimulants/metabolism , Cytochrome P-450 CYP1A2/drug effects , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Administration, Oral , Adult , Area Under Curve , Benzimidazoles/blood , Benzimidazoles/pharmacokinetics , Cross-Over Studies , Cytochrome P-450 CYP1A2/metabolism , Double-Blind Method , Drug Interactions , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Humans , Male , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/blood , Sulfoxides/pharmacokinetics , Xanthine Oxidase/metabolism
6.
Int J Clin Pharmacol Ther ; 36(10): 521-4, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9799054

ABSTRACT

OBJECTIVE: Pantoprazole is a H+/K+-ATPase inhibitor with a minimized potential of interaction with the cytochrome P450 system. Imidazole derivatives such as cimetidine and omeprazole have been shown to markedly interact with carbamazepine, a major anticonvulsant with a narrow therapeutic range. Therefore, the influence of steady-state pantoprazole on the pharmacokinetics of carbamazepine was investigated. SUBJECTS AND METHODS: N = 20 healthy volunteers (12 male/8 female) completed a double-blind, placebo-controlled, randomized crossover study. During the test period they received 40 mg pantoprazole p.o. once daily for 11 days and concomitantly a single oral dose of 400 mg carbamazepine on day 5. In the reference period placebo was administered instead of pantoprazole. RESULTS: Serum concentrations of carbamazepine and its active metabolite carbamazepine-10,11-epoxide were measured until day 11. Geometric means of AUC (extent characteristic) and Cmax/AUC (rate characteristic) of carbamazepine were 292 and 287 mgxh/l, and 0.0150 and 0.0144 l/h (reference and test), respectively. Point estimates and 90% confidence intervals of the ratios were 0.98 (0.95, 1.01) for AUC, and 0.96 (0.92, 1.00) for Cmax/AUC, respectively. Since the 90% confidence intervals of the primary characteristics, AUC and Cmax/AUC were entirely within the predefined equivalence range of 0.80 - 1.25, lack of interaction of pantoprazole with the pharmacokinetics of carbamazepine was demonstrated. Equivalence was also demonstrated for carbamazepine-10,11-epoxide using the characteristics AUC and Cmax. CONCLUSION: No dose adjustment of carbamazepine is therefore required during concomitant treatment with pantoprazole.


Subject(s)
Anticonvulsants/pharmacokinetics , Benzimidazoles/pharmacology , Carbamazepine/pharmacokinetics , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Anticonvulsants/adverse effects , Area Under Curve , Benzimidazoles/adverse effects , Biotransformation , Carbamazepine/adverse effects , Cross-Over Studies , Double-Blind Method , Drug Interactions , Enzyme Inhibitors/adverse effects , Female , Humans , Male , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/adverse effects
7.
Stroke ; 28(5): 1006-8, 1997 May.
Article in English | MEDLINE | ID: mdl-9158642

ABSTRACT

BACKGROUND AND PURPOSE: Ultrasound attenuation caused by the skull is a major limitation of transcranial Doppler. Echocontrast agents (EAs) may solve this problem. The aim of the present study was to investigate the characteristics of a new echocontrast agent (BY963) containing air bubbles stabilized by phospholipids. METHODS: Nine healthy volunteers received three different doses (2.5, 5.0, and 10 mL) of BY963 at an injection rate of 0.25 mL/s. The Doppler signal amplitude obtained from the middle cerebral artery was recorded with a 2-MHz pulsed-wave Doppler system. After complete decay of the signal enhancement, upward stroking of the veins of the upper arm was performed to evaluate the stability of the EA in the venous system. RESULTS: A dose-dependent increase of at least 30 dB in the Doppler signal amplitude lasted 19 to 47, 35 to 64, and 48 to 126 heart cycles (68% range) after 2.5, 5.0, and 10 mL EA, respectively. In 6 cases, there was a biphasic increase in EA enhancement. Upward stroking of the forearm, in general 12 to 18 minutes after administration, caused a Doppler signal enhancement of at least 30 dB in 6 cases. CONCLUSIONS: Each injection of BY963 caused a diagnostically relevant Doppler signal enhancement. A considerable amount of EA remained stable in the venous system for at least 12 minutes. The biphasic dose-response fits to models of dilution-indicator theory and indicates free recirculation, as well as a nonlinear washout curve.


Subject(s)
Contrast Media , Phosphatidylcholines , Ultrasonography, Doppler, Transcranial , Adult , Dose-Response Relationship, Drug , Female , Humans , Indicator Dilution Techniques , Male , Models, Theoretical
8.
Int J Clin Pharmacol Ther ; 34(10): 420-3, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8897078

ABSTRACT

The new H+/K+ ATPase inhibitor pantoprazole, a substituted benzimidazole, is metabolized by the hepatic cytochrome P450 enzymes 2C19 or 3A4 and subsequently undergoes phase II metabolism. The widely used beta 1-adrenoreceptor-blocking agent metoprolol is metabolized via CYP2D6. The influence of pantoprazole on the pharmacokinetics of an orally administered zero order kinetics formulation (ZOK) of metoprolol was the objective of this study. Eighteen volunteers (9 female, 9 male, age 20-44 years) completed the randomized, double-blind crossover study. Each subject received either 95 mg metoprolol and placebo (reference (R)) or 95 mg metoprolol and 40 mg pantoprazole (test (T)) as oral doses (sid) for 5 consecutive days. On day 5 of each period serum concentrations of R- and S-metoprolol were determined and a treadmill ergometry was performed. The primary pharmacokinetic characteristics for extent and rate of absorption were AUC(0-24h) and % PTF, respectively. To assess the pharmacodynamic effect of metoprolol the excess area under the effect vs. time curve was calculated for heart rate during ergometry (AUCexHR). Point estimate and 90% confidence limits (CI) for the ratios of population medians of T and R were given. The respective point estimates (90% CI) of the ratios of both primary and secondary characteristics were entirely within the equivalence range of 0.80 and 1.25 for both enantiomers of metoprolol. Moreover, equivalence could be shown for the pharmacodynamic characteristic AUCexHR. Hence, it was concluded that pantoprazole does not interact with metoprolol pharmacokinetics or pharmacodynamics. Therefore, no dose adjustment of metoprolol during therapy with pantoprazole is necessary.


Subject(s)
Adrenergic beta-Antagonists/pharmacokinetics , Anti-Ulcer Agents/pharmacology , Benzimidazoles/pharmacology , Metoprolol/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Administration, Oral , Adrenergic beta-Antagonists/administration & dosage , Adrenergic beta-Antagonists/pharmacology , Adult , Anti-Ulcer Agents/administration & dosage , Benzimidazoles/administration & dosage , Blood Chemical Analysis , Cross-Over Studies , Double-Blind Method , Drug Interactions , Exercise Test , Female , Heart Rate/drug effects , Humans , Male , Metoprolol/administration & dosage , Metoprolol/blood , Metoprolol/pharmacology , Omeprazole/analogs & derivatives , Pantoprazole , Stereoisomerism , Sulfoxides/administration & dosage
9.
Br J Clin Pharmacol ; 42(2): 249-52, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8864328

ABSTRACT

Pantoprazole, a substituted benzimidazole, is a potent and well tolerated inhibitor of the gastric H+,K(+)-ATPase with a low potential to inhibit cytochrome P450. In this randomized, placebo-controlled two-period crossover study, 12 healthy volunteers received placebo (reference) and 240 mg of pantoprazole (test) i.v. within 2 min once daily for 7 days each. On day 4 of either period, a 1 min bolus of diazepam (0.1 mg kg-1 body weight) was additionally injected. Pantoprazole was well tolerated and did not cause clinically relevant changes in heart rate, blood pressure, ECG and routine clinical laboratory parameters. There was no effect on diazepam clearance (0.021 1 h-1 kg-1 for test and reference) and elimination half-life (36.8 for test, 40.4 h for reference). Diazepam metabolism to desmethyldiazepam was not affected by pantoprazole. In conclusion, pantoprazole and diazepam may be administered concomitantly without dose adjustment even when high doses of pantoprazole are required.


Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Anti-Ulcer Agents/pharmacology , Benzimidazoles/pharmacology , Diazepam/pharmacokinetics , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Area Under Curve , Benzimidazoles/adverse effects , Blood Pressure/drug effects , Cross-Over Studies , Diazepam/adverse effects , Drug Interactions , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/adverse effects
10.
Int J Clin Pharmacol Ther ; 34(6): 243-62, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8793611

ABSTRACT

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Various mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In contrast to omeprazole, pantoprazole has a low potential to interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, substrates for all relevant cytochrome P450 families involved in the metabolism of drugs in man were investigated. Pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, a hormonal contraceptive (combination of levonorgestrel and ethinylestradiol), metoprolol, nifedipine, phenprocoumon, phenytoin, theophylline and warfarin in man. Pantoprazole also neither induced the metabolism of antipyrine or caffeine, nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.


Subject(s)
Benzimidazoles/adverse effects , Enzyme Inhibitors/adverse effects , Proton Pump Inhibitors , Sulfoxides/adverse effects , 2-Pyridinylmethylsulfinylbenzimidazoles , Benzimidazoles/pharmacokinetics , Drug Interactions , Enzyme Inhibitors/pharmacokinetics , Humans , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/pharmacokinetics
11.
Aliment Pharmacol Ther ; 10(3): 359-66, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8791964

ABSTRACT

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzyme system in man. Its effect on intragastric pH following single and repeated oral intake was investigated in comparison to omeprazole by continuous intragastric pH-metry at doses recommended for treatment of peptic ulcer disease. METHODS: Sixteen healthy male subjects underwent two dosing periods. From day 1 to day 7, they were given once daily by mouth 40 mg pantoprazole in one period and 20 mg omeprazole in the other period, according to a double-blind randomized crossover design. Twenty-four-hour intragastric pH was recorded and frequent blood samples for pharmacokinetic analysis were taken on day 1 and day 7. A placebo pH profile was obtained prior to each treatment period. RESULTS: Pantoprazole was significantly more effective than omeprazole with regard to increase in 24-h and daytime pH, following both single (median 24-h pH: 1.45 vs. 1.3, P < 0.05; median daytime pH: 1.6 vs. 1.3, P < 0.01) and repeated (median 24-h pH: 3.15 vs. 2.05, P < 0.01; median daytime pH: 3.8 vs. 2.65, P < 0.05) oral intake. As compared to the first dose, repeated administration of both drugs markedly increased the effect on intragastric pH. With pantoprazole, steady-state serum concentrations were obtained after the first dose, but not with omeprazole. Both drugs were well tolerated without relevant changes in vital signs of clinical laboratory parameters. CONCLUSION: Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in raising intragastric pH.


Subject(s)
Benzimidazoles/pharmacology , Benzimidazoles/pharmacokinetics , Circadian Rhythm/physiology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Gastric Acid/metabolism , Omeprazole/pharmacology , Omeprazole/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacology , Sulfoxides/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Area Under Curve , Benzimidazoles/administration & dosage , Circadian Rhythm/drug effects , Cross-Over Studies , Diet , Enzyme Inhibitors/administration & dosage , Gastric Acidity Determination , Half-Life , Humans , Male , Omeprazole/administration & dosage , Pantoprazole , Sulfoxides/administration & dosage
12.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S7-16, 1996 May.
Article in English | MEDLINE | ID: mdl-8793599

ABSTRACT

The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.


Subject(s)
Benzimidazoles/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles , Adolescent , Adult , Aged , Benzimidazoles/administration & dosage , Enzyme Inhibitors/administration & dosage , Female , Humans , Male , Middle Aged , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/administration & dosage
13.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S18-24, 1996 May.
Article in English | MEDLINE | ID: mdl-8793600

ABSTRACT

Pantoprazole is a specific inhibitor of the H+/K(+)-ATPase of the gastric parietal cell. The dose-dependency of a range of pantoprazole pharmacokinetic characteristics was studied. Twelve healthy male subjects were given 10, 20, 40 and 80 mg pantoprazole intravenously according to a randomized, single blind, 4-period change-over scheme. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with the dose. Apparent volume of distribution (Vd area), clearance (Cl) and terminal half-life (t1/2) were independent of the dose. The dose-independent elimination of pantoprazole was attributed to the lack of interaction of the drug with cytochrome P450. In clinical practice, a good predictable response, as well as a low potential for interaction with other drugs might be expected.


Subject(s)
Benzimidazoles/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Area Under Curve , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Half-Life , Humans , Injections, Intravenous , Male , Omeprazole/analogs & derivatives , Pantoprazole , Regression Analysis , Single-Blind Method , Sulfoxides/administration & dosage , Sulfoxides/adverse effects
14.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S31-50, 1996 May.
Article in English | MEDLINE | ID: mdl-8793602

ABSTRACT

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Various mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In contrast to omeprazole, pantoprazole has a low potential to interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, substrates for all relevant cytochrome P450 families involved in the metabolism of drugs in man were investigated. Pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, a hormonal contraceptive (combination of levonorgestrel and ethinylestradiol), metoprolol, nifedipine, phenprocoumon, phenytoin, theophylline and warfarin in man. Pantoprazole also neither induced the metabolism of antipyrine or caffeine, nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.


Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Benzimidazoles/pharmacokinetics , Drug Interactions , Enzyme Inhibitors/pharmacokinetics , Humans , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/pharmacokinetics
15.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S51-7, 1996 May.
Article in English | MEDLINE | ID: mdl-8793603

ABSTRACT

The potential influence of pantoprazole (BY1023/SK&F96022), a newly developed selective inhibitor of the gastric H+,K(+)-ATPase, on therapeutic serum theophylline concentrations was investigated in a crossover study in 8 healthy male volunteers (age 25-30 [median 27] years, body weight 63-80 [median 68] kg). Steady-state serum theophylline concentrations were obtained by a two-step intravenous infusion scheme of approximately 350 mg theophylline each over 0.5 h and subsequently over approximately 10 h, respectively. In the test period, 30 mg pantoprazole were injected over 2 min on 5 consecutive days and theophylline was infused on day 4. In the reference period, placebo was administered i.v. on 2 consecutive days and theophylline on day 1. Serum pantoprazole concentrations were measured up to 12 h, serum theophylline concentrations up to 36 h. Pantoprazole was well tolerated with and without theophylline. There were no clinically relevant changes in blood pressure, heart rate, ECG and routine clinical laboratory parameters. Primary characteristic for confirmative assessment of no interaction was the area under the concentration/time curve (AUC). Lack of interaction in the sense of equivalence was concluded both for theophylline (with and without pantoprazole) and pantoprazole (with and without theophylline), as the 90%-confidence intervals of the AUC-ratio test/reference were within the equivalence range of 0.8 to 1.25. Further explorative analysis of theophylline disposition kinetics revealed this inclusion also for clearance and volume of distribution, but not for the half-life. In the case of pantoprazole, the corresponding 90%-confidence intervals for any of the secondary characteristics clearance, volume of distribution and half-life were within the above mentioned range. In conclusion, repeated once-daily i.v. injections of 30 mg pantoprazole have no clinically relevant influence on steady-state theophylline serum concentrations, nor does theophylline at therapeutic serum concentrations influence the pantoprazole disposition kinetics. Hence, in clinical practice theophylline and pantoprazole can be administered concomitantly without dose adjustment.


Subject(s)
Benzimidazoles/pharmacology , Bronchodilator Agents/pharmacokinetics , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , Theophylline/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Area Under Curve , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Bronchodilator Agents/blood , Bronchodilator Agents/pharmacology , Cross-Over Studies , Drug Interactions , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Infusions, Intravenous , Male , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/adverse effects , Sulfoxides/pharmacokinetics , Theophylline/blood , Theophylline/pharmacology
16.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S58-66, 1996 May.
Article in English | MEDLINE | ID: mdl-8793604

ABSTRACT

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC-and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study. The corresponding 90%-confidence intervals were all within the equivalence range of 0.8-1.25 so that lack of interaction either by inhibition or induction can be concluded.


Subject(s)
Analgesics, Non-Narcotic/pharmacokinetics , Antipyrine/pharmacokinetics , Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Administration, Oral , Adult , Analgesics, Non-Narcotic/blood , Antipyrine/blood , Area Under Curve , Biotransformation , Chromatography, High Pressure Liquid , Cross-Over Studies , Drug Interactions , Half-Life , Humans , Injections, Intravenous , Male , Omeprazole/analogs & derivatives , Pantoprazole , Spectrophotometry, Ultraviolet , Therapeutic Equivalency
17.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S67-71, 1996 May.
Article in English | MEDLINE | ID: mdl-8793605

ABSTRACT

Substituted benzimidazole inhibitors of the gastric H+/K+ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs. On the other hand, changes in intragastric pH might alter the absorption of other drugs. The primary aim of the present study was to determine whether pantoprazole modifies the steady-state serum concentrations of orally administered digoxin. Secondary aims were the influence of digoxin on the pharmacokinetics of pantoprazole as well as safety and tolerability. Eighteen healthy volunteers received a single oral dose of pantoprazole (40 mg) and serum concentrations were determined. Three to 10 days later, subjects received in a single-blind, randomized, crossover fashion oral beta-acetyldigoxin (0.2 mg) twice daily and concomitant oral pantoprazole (40 mg) or placebo once daily for 5 days. Serum concentrations of pantoprazole and digoxin were determined on day 5. Primary characteristics for confirmative assessment of no interaction were AUC and Cmax of digoxin. Lack of interaction in the sense of equivalence was concluded for both digoxin (with and without pantoprazole) and pantoprazole (with and without digoxin) as the 90%-confidence intervals of the respective AUC- and Cmax-ratios were within the equivalence range of 0.8-1.25. Pantoprazole did not influence the characteristic ECG modifications (T-wave) caused by digoxin. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or clinical laboratory parameters were observed during treatment. In conclusion, pantoprazole and digoxin may be administered concomitantly without the need for dose adjustment.


Subject(s)
Benzimidazoles/pharmacology , Cardiotonic Agents/pharmacokinetics , Digoxin/pharmacokinetics , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Area Under Curve , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Cardiotonic Agents/adverse effects , Cardiotonic Agents/pharmacology , Cross-Over Studies , Digoxin/adverse effects , Digoxin/pharmacology , Drug Interactions , Electrocardiography/drug effects , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Male , Omeprazole/analogs & derivatives , Pantoprazole , Single-Blind Method , Sulfoxides/adverse effects , Sulfoxides/pharmacokinetics
18.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S72-5, 1996 May.
Article in English | MEDLINE | ID: mdl-8793606

ABSTRACT

Twenty-three healthy, male volunteers completed this doubleblind, randomized, placebo controlled, 2-period crossover study to assess the influence of multiple doses of pantoprazole on single-dose phenytoin pharmacokinetics. During each treatment period, the volunteers received either one 40 mg pantoprazole tablet or placebo for 7 days. In addition, a single-dose of 300 mg (3 x 100 mg capsules) phenytoin sodium was administered on day 4 of each treatment period. A 14-day wash-out period was allowed between phenytoin administrations. The results indicate that pantoprazole neither affects the rate nor the extent of absorption, nor the elimination of phenytoin.


Subject(s)
Anticonvulsants/pharmacokinetics , Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Phenytoin/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adolescent , Adult , Anticonvulsants/adverse effects , Area Under Curve , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Cross-Over Studies , Double-Blind Method , Drug Interactions , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Half-Life , Humans , Male , Omeprazole/analogs & derivatives , Pantoprazole , Phenytoin/adverse effects , Sulfoxides/administration & dosage , Sulfoxides/adverse effects
19.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S76-80, 1996 May.
Article in English | MEDLINE | ID: mdl-8793607

ABSTRACT

The new H+/K+ ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles may potentially interact with the cytochrome P450 system, the influence of pantoprazole on the pharmacokinetics of the NSAID diclofenac was investigated. Diclofenac is widely used in the treatment of rheumatic diseases and is mainly metabolized in the liver by CYP2C9. Twenty-four healthy volunteers (13 male/11 female) completed a randomized crossover study. As test they received orally 40 mg pantoprazole and concomitantly 100 mg diclofenac. As respective references 100 mg diclofenac or 40 mg pantoprazole were given alone. Diclofenac and pantoprazole serum concentrations were measured. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90% confidence intervals (CI) of the ratios of the primary characteristic AUC and the secondary characteristic Cmax of diclofenac were entirely within the equivalence range of 0.8-1.25. Hence, no influence of pantoprazole on the pharmacokinetics of diclofenac was concluded, either by competition with the CYP2C9 or by the reduction of gastric acid secretion. Vice versa, diclofenac did not affect the pharmacokinetics of pantoprazole. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with diclofenac and pantoprazole.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Ulcer Agents/pharmacology , Anticonvulsants/pharmacokinetics , Benzimidazoles/pharmacology , Diclofenac/pharmacokinetics , Enzyme Inhibitors/pharmacology , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Ulcer Agents/pharmacokinetics , Anticonvulsants/adverse effects , Area Under Curve , Benzimidazoles/pharmacokinetics , Cross-Over Studies , Diclofenac/pharmacology , Double-Blind Method , Drug Interactions , Enzyme Inhibitors/pharmacokinetics , Female , Half-Life , Humans , Male , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/pharmacokinetics
20.
Int J Clin Pharmacol Ther ; 34(1 Suppl): S81-5, 1996 May.
Article in English | MEDLINE | ID: mdl-8793608

ABSTRACT

The new H+/K(+)-ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles can interact with the cytochrome P450 system, the influence of pantoprazole on the steady-state pharmacokinetics of the calcium antagonist nifedipine was investigated. Nifedipine is widely used in the treatment of cardiovascular diseases and is mainly metabolized in the liver by CYP3A4. Additionally possible influence of gastric pH on the absorption of nifedipine is discussed. Twenty-four healthy volunteers (13 m/11 f) completed a randomized crossover study. As test they received orally 40 mg pantoprazole s.i.d. for 10 days and concomitantly 20 mg nifedipine sustained release (SR) b.i.d. from day 6 to 10. During the reference period 20 mg nifedipine SR were dosed b.i.d. for 5 days. Nifedipine and pantoprazole serum concentrations were measured over one dosing interval on the last day of each period. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90%-confidence intervals (CI) of the ratios of the primary characteristics AUC and Cmax of nifedipine were entirely within the equivalence range of 0.8-1.25. Hence no influence of pantoprazole on the pharmacokinetics of nifedipine was concluded, either by competition with the CYP3A4 or by the reduction of gastric acid secretion. As secondary criterion nifedipine had no relevant influence on the pantoprazole pharmacokinetic characteristics. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with nifedipine and pantoprazole.


Subject(s)
Anti-Ulcer Agents/pharmacology , Anticonvulsants/pharmacokinetics , Benzimidazoles/pharmacology , Calcium Channel Blockers/pharmacokinetics , Enzyme Inhibitors/pharmacology , Nifedipine/pharmacokinetics , Proton Pump Inhibitors , Sulfoxides/pharmacology , 2-Pyridinylmethylsulfinylbenzimidazoles , Adult , Anti-Ulcer Agents/pharmacokinetics , Anticonvulsants/adverse effects , Area Under Curve , Benzimidazoles/pharmacokinetics , Blood Pressure/drug effects , Calcium Channel Blockers/pharmacology , Drug Interactions , Electrocardiography/drug effects , Enzyme Inhibitors/pharmacokinetics , Female , Half-Life , Heart Rate/drug effects , Humans , Male , Nifedipine/pharmacology , Omeprazole/analogs & derivatives , Pantoprazole , Sulfoxides/pharmacokinetics
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