Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.

OBJECTIVE: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. METHODS: Subjects (n = 16) received single oral roflumilast 500 microg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 - 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. RESULTS: After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. CONCLUSIONS: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.

Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects.

OBJECTIVE: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating beta2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects. METHODS: In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 microg once daily, orally inhaled salbutamol 200 microg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments. RESULTS: Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0-24 h (AUC 0-24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC 0-24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC 0-6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated. CONCLUSION: There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses.

Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar.

OBJECTIVE: To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. METHODS: 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 microg (ex-actuator, equivalent to 1,600 microg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry. RESULTS: There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC(0 - inf)) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t1/2) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups. CONCLUSION: After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.

Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide.

Ciclesonide, an inhaled corticosteroid (ICS) with prolonged anti-inflammatory activity, is being developed for the treatment of asthma. Fatty acid conjugation of ICS is thought to be related to prolonged ICS activity. In vitro studies demonstrated that ciclesonide is converted to an active metabolite, desisobutyryl-ciclesonide (des-CIC), which undergoes reversible fatty acid conjugation. We tested the in vivo metabolism of ciclesonide in the lung by exposing rats to inhaled ciclesonide (0.16 mg/kg/day) for 1h daily over 4 weeks. Lungs (n=6 per time point) were extracted with ethanol 2, 5, and approximately 27 h after the final treatment. Ciclesonide and des-CIC concentrations were determined using solid-phase extraction and reverse-phase high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS). Concentrations of fatty acid ester conjugates were indirectly assessed using enzymatic de-esterification before LC/MS/MS. At 2 and 5 h, fatty acid conjugates of des-CIC were the major metabolites (61 and 55%, respectively). Ciclesonide, des-CIC, and fatty acid conjugates of des-CIC were clearly present in lung samples the day after the last inhalation. This in vivo study confirmed ciclesonide activation to des-CIC and formation of fatty acid conjugates. The presence of des-CIC fatty acid conjugates at >24 h after dosing suggests that ciclesonide is appropriate for once-daily dosing.

Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin.

OBJECTIVE: To investigate whether systemic exposure to desisobutyrylciclesonide (des-CIC) (the pharmacologically active metabolite of ciclesonide) and erythromycin are affected by combined administration of ciclesonide and erythromycin. METHODS: 18 healthy subjects were enrolled in a Phase 1, open-label, randomized, three-period crossover study. Each subject received ciclesonide (640 microg ex-actuator, equivalent to 800 microg ex-valve, via hydrofluoroalkane metered-dose inhaler) and erythromycin (500 mg PO), separately and in combination, in random order. Blood samples were collected at timed intervals to determine serum concentrations of erythromycin, des-CIC, and ciclesonide using HPLC-MS detection. Adverse events were recorded throughout the study. RESULTS: Combined administration of ciclesonide and erythromycin did not alter the pharmacokinetics (PK) of either drug. The serum concentration vs. time profiles of erythromycin, des-CIC, and ciclesonide were similar when ciclesonide and erythromycin were administered separately or together. In addition, the PK characteristics of erythromycin and des-CIC were equivalent following single or co-administration. Point estimates (90% confidence intervals (CI)) for erythromycin were as follows: AUC0-inf, 0.96 (0.79, 1.18); Cmax, 1.00 (0.84, 1.20); and t1/2, 0.96 (0.83, 1.12). The following point estimates (90% CI) were obtained for des-CIC: AUC0-inf, 1.16 (1.03, 1.30); Cmax, 1.06 (0.98, 1.15); and t1/2, 1.04 (0.96, 1.13). Lack of ciclesonide/erythromycin interaction was demonstrated as the 90% CI of AUC0-inf, Cmax, and t1/2 of both compounds were entirely within the stipulated equivalence range of 0.67 - 1.50. No study drug-related adverse events occurred during this study. CONCLUSIONS: Combined administration of ciclesonide and erythromycin did not alter the PK properties of either drug. Both drugs were safe and well-tolerated. Therefore, systemic exposure to ciclesonide or erythromycin is not increased in patients receiving concomitant therapy.

Identification of enzymes involved in phase I metabolism of ciclesonide by human liver microsomes.

Ciclesonide, a novel inhaled corticosteroid, is currently being developed for the treatment of asthma. Here, the enzymes catalysing the human hepatic metabolism of ciclesonide were investigated. When incubated with human liver microsomes (HLM), [14C]ciclesonide was first metabolised to the active metabolite M1 (des-isobutyryl-ciclesonide, des-CIC) and to at least two additional metabolites, M2 and M3. M3 comprises a 'family' of structurally similar metabolites that are inactive. 16-Hydroxyprednisolone was also formed in microsomal incubations of [14C]des-CIC, but at approximately one-tenth the amount of both M2 and M3. bis-p-Nitrophenylphosphate and SKF 525-A respectively inhibited des-CIC formation from [14C]ciclesonide by 82% and 49% and M2/M3 formation by 82-84% and 87-89%. Regression analysis showed significant negative correlations (r = -0.96, -0.79 and -0.71, respectively) of M2 formation with CYP3A4/5, CYP2B6 and CYP2C8 activities; M3 formation significantly correlated with CYP4A9/11 (r = 0.47). Troleandomycin and diethyldithiocarbamate inhibited M2 and M3 formation by 85% and 45%, respectively. Sulphaphenazole and quinidine had no inhibitory effects. CYP3A4 Supersomes catalysed notable formation of both M2 and M3 from [14C]des-CIC; CYP2C8 and CYP2D6, but not CYP4A11 formed smaller amounts. It is concluded that the human hepatic metabolism of ciclesonide is primarily catalysed by one or more esterases and, subsequently, by CYP3A4.

Population pharmacokinetics and pharmacodynamics of ciclesonide.

Ciclesonide is a novel glucocorticoid that is converted into ciclesonide--active principle (CIC-AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC-AP using nonlinear mixed-effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD) parameters, and investigate the effects of CIC-AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400-3600 micrograms) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC-AP population PK analysis. Various models examined inter- and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% co-efficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC-AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC-AP can be described using mixed-effect modeling. The estimated EC50 is similar to mean Cmax from an 800-micrograms dose, further suggesting CIC-AP has little effect on cortisol suppression.

Dose linearity and steady state pharmacokinetics of the new antiparkinson agent budipine after oral administration.

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg single dose. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with ascending doses of orally given budipine. Time to maximum serum concentration (tmax) and terminal half-life (t1/2) were independent of the administered dose. As compared to the 10 mg single dose pharmacokinetics, the repeated oral administration of budipine 10 mg t.i.d. resulted in an increase in AUC of 11% and 93% for budipine and its metabolite p-OH-budipine, respectively. In clinical practice, a predictable response in proportion to the dose is to be expected.

Pantoprazole lacks induction of CYP1A2 activity in man.

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.

Development of a small-scale bioreactor for drug metabolism studies maintaining hepatospecific functions.

1. The aim of the study was the development of a small-scale liver cell bioreactor maintaining tissue monoxygenase activity and hepatospecific activities over at least 2 weeks. 2. For characterization the antihypertensive drug urapidil was used as a model compound to study maintenance of metabolic activity. Tissue-specific parameters assessed included urea and albumin secretion as well as cellular integrity. The problem of the use of serum in bioreactor cultures is addressed. 3. Bioreactor runs could be performed in serum- and lactate-free cultures with a joint recovery of oxidative biotransformation capacity for urapidil as well as tissue-specific markers. LDH release was reduced with older cultures. Fibronectin was shown as a contributing factor for cell attachment. 4. In the present study the design and function of a modular, small-scale-type bioartificial liver cell culture model is thus described lending itself for drug metabolism studies but maintaining also typical hepatospecific properties.

Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration.

PURPOSE: To investigate distribution and excretion of mangafodipir (MnDPDP, Teslascan) in the rat and dog. MATERIAL AND METHODS: Formulations of either 14C-MnDPDP or 54MnDPDP were injected intravenously at near clinical doses in rats and dogs. RESULTS: The manganese (Mn) moiety is rapidly removed from plasma with an elimination half-life of less than 25 min in both species, reflecting a rapid distribution to the tissues and an early excretion. The plasma clearance of the DPDP moiety is slower than that of Mn and it appears to distribute into the extracellular fluid. Mn is distributed largely to the liver, pancreas and kidneys, and in pregnant rats, also to foetal liver and bones. No transplacental passage of DPDP could be detected. The metal is mainly excreted by the faecal route, with a small fraction eliminated early in the urine. DPDP is rapidly and essentially completely excreted in the urine, consistent with the glomerular filtration rate. CONCLUSION: The ligand does not appear to facilitate the transport of Mn into any organ except the kidney for subsequent excretion, and it reduces distribution to the heart. The Mn is taken up by those organs indicated for MR imaging, primarily liver and pancreas.

Phase I and pharmacokinetic study of the P-glycoprotein modulator dexniguldipine-HCL.

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

Lack of pantoprazole drug interactions in man: an updated review.

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.

Pharmacokinetics and drug interactions--relevant factors for the choice of a drug.

Pharmacokinetics serve as a useful tool in drug development by identifying the drug's disposition and elimination characteristics, the absorption characteristics of the biopharmaceutical formulation, and the therapeutic dose regimen in various patient populations. Where two or more drugs of a class have a similar efficacy, the choice of the drug may depend upon the reproducibility of the pharmacokinetics and the minimal risk of drug interaction. Pantoprazole, a selective proton pump inhibitor, appears to meet the above criteria. As opposed to other members of the class, pantoprazole exhibits linear, predictable pharmacokinetics and lack of drug interactions.

Pharmacokinetics of pantoprazole in man.

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.

Lack of pantoprazole drug interactions in man: an updated review.

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.

Pharmacokinetics of pantoprazole in man.

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(O,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 halflife 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.

Tolerance, safety, and kinetics of the new antineoplastic compound dexniguldipine-HCl after oral administration: a phase I dose-escalation trial.

Dexniguldipine-HCl is a new dihydropyridine compound that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. The purpose of this trial was to determine the toxicity and pharmacokinetics of dexniguldipine and to establish a recommended dose for phase II trials. A total of 37 patients with cancer were treated with oral dexniguldipine in increasing doses for up to 7 days. The main parameters evaluated were subjective tolerance and laboratory and cardiovascular parameters (blood pressure and ECG). Blood samples were drawn for analysis of the drug's pharmacokinetics. Dizziness and nausea were the major adverse events observed in seven patients, but episodes were generally mild and not clearly dose-related. Vomiting occurred in one patient. Hypotensive effects and orthostatic dysregulation were observed in some patients but were not considered to be dose-limiting. Therefore, no dose-limiting toxicity was found and the maximally tolerable dose could not be determined. Pharmacokinetic data showed wide interindividual variation and a dose-dependent increase in steady-state serum concentrations at doses of up to 1,000 mg daily, with no clear further increase being observed at higher doses. Consistently high concentrations were achieved with the 2,500-mg dose. Despite the lack of dose-limiting toxicity, higher doses of dexniguldipine do not appear to be useful for clinical evaluation because of the pharmacokinetic properties of the compound: therefore, 2,500 mg/day is recommended as the daily dose for phase II trials.

Lack of pantoprazole drug interactions in man.

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Different 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 comparison to omeprazole and lansoprazole, pantoprazole showed a much lower affinity to cytochrome P450 in vitro and a markedly lower potency in the in vivo rat model for interaction with diazepam. In contrast to omeprazole, pantoprazole does not interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, diazepam, digoxin, a hormonal contraceptive, nifedipine, phenytoin, theophylline and warfarin in man. Also pantoprazole neither induced the drug metabolism of antipyrine 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.

Use of organotypical cultures of primary hepatocytes to analyse drug biotransformation in man and animals.

1. In conventional single-gel culture systems for primary hepatocytes, rapid loss of drug metabolizing capacities is a common feature and parallels general loss of function. An organotypical (double gel) culture technique for primary hepatocytes is established by enclosing the cells within two layers of extra cellular matrix. This serves to imitate the in vivo microenvironment within the space of Dissé. Using rat hepatocytes, this technique has been shown previously to maintain protein synthetic functions in vitro and to allow more efficient P450A-dependent biotransformation of drugs than a standard single-gel culture system. 2. The aim was to test the capacity of this organotypical culture model for primary rat and human hepatocytes to generate drug metabolites in a typical species-dependent pattern. 3. Urapidil, an antihypertensive drug, was used as a test compound, since it is metabolized in vivo in a species-dependent manner in rat and man. 4. Primary rat and human hepatocytes were cultured within two layers of collagen and exposed to 2.25 micrograms/ml urapidil for periods of 1-24 h at 3 days in culture. Urapidil metabolites were measured using hplc. 5. Metabolite M1 (hydroxylated product) was produced preferentially in human hepatocyte cultures, and metabolites M2/M3 (O-demethylated, N-demethylated product) were preferentially generated in rat cultures. This corresponded to the in vivo pattern found in man and rat, respectively. 6. Since in vitro urapidil metabolism by human and rat hepatocytes cultured in a double-gel system reflects that in vivo, it is suggested that information from such a system may be useful to predict the metabolic pathway of novel xenobiotics and to direct further toxicological evaluation.