Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study.

Administering codeine to breast-feeding mothers had been considered safe until the recent death of a breast-fed neonate whose mother had been prescribed codeine. We investigated the risk of opioid poisoning to breast-fed neonates using coupled physiologically based pharmacokinetic models for the mother and child. Neonatal morphine plasma concentrations were simulated for various combinations of cytochrome P450 2D6 (CYP2D6) genotype and morphine clearance, assuming typical breast-feeding schedules and maternal codeine doses of

Capillary electrophoresis with laser-induced fluorescence in clinical drug development routine application and future aspects.

The clinical bioanalytical setting is characterized by sample volumes of < 1 ml biological fluid (e.g. plasma, urine), a range of 3-4 decades of concentrations to be quantified and a limit of quantitation in the microg/l-ng/l range for sets of 100-5000 individual samples. Setup of capillary electrophoresis (CE) for routine application in this analytical field was successful for analytes accessible to fluorescence detection by using laser-induced fluorescence (LIF) detection. Empowerment of CE-LIF for routine serial analysis of thousands of samples includes improvement in autosampler techniques, thorough procedures for capillary treatment and particularly more advanced detection technology. Introduction of multi-capillary systems with charge-coupled device cameras and frequency doubled Ar-ion laser (lambda = 257 nm) offers this technique the chance of superiority over classical analytical assays - especially in the field of (new) low volume samples e.g. capillary blood or microdialysate encouraging clinicians to search for meaningful non-invasive samples.

Guidances related to bioavailability and bioequivalence: European industry perspective.

The investigations of bioavailability and bioequivalence can be classified according to three separate areas of information. Firstly, estimation of bioavailability judged on a drug substance's in vivo characteristics taking into account solubility, polymorphism, stability (especially under the conditions of the GI tract), gut wall permeability and first pass metabolism. Secondly, evaluation of formulation properties including dissolution profile in the GI tract and its contribution to exposure variability with respect to the desired absorption characteristics. Finally, maintaining quality during the market phase with respect to equivalence to the clinical trial formulations. While in the first two areas, the range of the estimated mean values and the intra- and inter-subject variabilities contain the desired information for proper medical decisions, in the third area the mean values and their confidence limits describe the quality with regard to the formulations of proven efficacy. Guidelines should clearly distinguish between the different areas in their recommendations regarding the intended information, e.g. mean values and/or ranges and confidence intervals. New approaches of granting limited waivers for BE studies (e.g. Biopharmaceutical Classification System (BCS)) should be expanded to consideration of pharmacokinetic properties of drugs (e.g. gastrointestinal metabolism, evidence for an absorption window, magnitude of first-pass effect, half-life) as already partly implemented in the German waiver concept, and further (scientifically) validated to achieve world-wide harmonisation (e.g. via ICH).

The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine.

OBJECTIVE: The primary aim of the present study was to investigate the effect of ketoconazole on the pharmacokinetics of nisoldipine. METHODS: A single dose of nisoldipine 5 mg immediate-release tablet was administered either alone or in combination with ketoconazole 200 mg (4 days pretreatment and concomitant administration) in a randomized crossover trial in seven healthy male Caucasian volunteers. Plasma concentration-versus-time profiles of nisoldipine and its metabolite M9 were determined. RESULTS: Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold, increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. The ketoconazole-induced increase in plasma concentration of the metabolite M9 was of similar magnitude. CONCLUSION: The interaction is attributed to inhibition of cytochrome 3A4-mediated first-pass metabolism. Ketoconazole and other antifungal drugs of the substituted imidazole type as well as other potent inhibitors of cytochrome 3A4 should not be used concomitantly with nisoldipine.

Determination of nifedipine in human plasma by flow-injection tandem mass spectrometry.

For use in clinical studies, a fast and sensitive assay method was developed for the determination of nifedipine in human plasma samples. The assay method is based on tandem mass spectrometry detection (HPLC-MS-MS). The effect of flow injection as well as HPLC separation on the results of the nifedipine determination were evaluated. The limit of quantification is 0.5 ng/ml and the accuracy (as determined by spiking recovery) was found to be good.

Inter-ethnic comparisons of the pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.

AIMS: During the world-wide clinical development of the HMG-CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter-ethnic differences in cerivastatin pharmacokinetics. METHODS: All concentration data were assessed by fully validated specific h.p.l.c. assays employing post-column photochemical derivatization with ultra-violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross-validations between all analytical laboratories. The inter-ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n = 340 complete profiles) in the key parameters AUC, Cmax, tmax and t1/2, assessed via non-compartmental methods. RESULTS: Based on the comparison of selected individual single- and multiple-dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450-mediated biotransformation products M-1 and M-23, and amounts of metabolites M-1, M-23 and M-24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose-normalized AUC- and Cmax-values. The respective ratios of weight-adjusted geometric least-squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUCdose-norm 0.96 (0.86-1.08) for single dose, and 1.04 (0.86-1.24) for multiple dose; for Cmax,dose-norm 0.93 (0.83-1.05) for single dose, and 1.01 (0.82-1.25) for multiple dose. Half-life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61-0.77) for single dose, and 1.00 (0.79-1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight-adjusted LS means (95% CI) were 0.60 h (0.28 h-0.92 h) for single dose, and 1.15 h (0.48 h-1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians. CONCLUSIONS: Based on inter-study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter-ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.

Pharmacokinetics of the controlled-release nisoldipine coat-core tablet formulation.

UNLABELLED: The pharmacokinetics, safety, and tolerability of the novel once-daily "coat-core" formulation of the calcium antagonist nisoldipine were investigated in 4 randomized nonblind studies A-D in 52 healthy volunteers. Immediate-release or intravenous formulations were administered as reference in 3 studies. The objective of the present studies was to select the optimum controlled-release formulation (A), compare it to the immediate-release tablet at steady-state (B), determine the absolute bioavailability (C), and investigate bioequivalence after a small change in composition (D). Comparative pharmacokinetic properties: Mean residence time and apparent terminal half-life of nisoldipine in the coat-core formulation were significantly increased in comparison to administration via the intravenous route or the oral immediate-release formulation. Concentration profiles could be described with a 3-segment input model. Steady-state conditions were established with the second dose of nisoldipine coat-core and accumulation from first dose to steady-state accounted for 46% as expected due to the contribution of AUC beyond 24 h. At steady-state the coat-core formulation produced a plateau-shaped profile of nisoldipine plasma concentrations throughout the 24 h dosing interval and the peak-trough fluctuation was reduced by approximately 4-fold, compared to the immediate-release tablet in a b.i.d. regimen. While the absolute bioavailability of the drug in the coat-core tablet was 5.5%, its relative bioavailability was greater by 1.5-fold compared to the immediate-release tablet. This can be attributed to release of drug in the colon where the contribution of the gut wall to presystemic metabolism is reduced resulting in an increase in bioavailability as compared to stomach and small intestine. The intersubject variability of nisoldipine coat-core pharmacokinetics was comparable to that of the immediate-release tablet. The within-subject (intraindividual) variability was considerably smaller. Based on its pharmacokinetic profile the side chain-hydroxylated metabolite M 9 is not expected to contribute significantly to the antihypertensive effect of nisoldipine coat-core. In vitro/in vivo correlation: There was a rank order correlation between in vitro release rate of 3 different nisoldipine coat-core formulations and their noncompartmental pharmacokinetic parameters, a decrease in dissolution rate leading to increased bioavailability in vivo. Likewise, the mean dissolution times in vitro and in vivo were correlated in rank order. A linear (level A) correlation could be established within approximately 0-6 hours (in vitro) corresponding to 0-12 hours in vivo. The change in slope of the correlation curve after approximately 12 hours (in vivo) most likely reflects changes in both rate and extent of nisoldipine absorption in different sections of the gastrointestinal tract. SAFETY: In the present studies the drug was safe and well tolerated, adverse events related to peripheral vasodilatation being less frequent with the coat-core tablet compared to intravenous or immediate-release formulations.

Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin.

To determine the absolute bioavailability of the HMG-CoA reductase inhibitor cerivastatin, 12 healthy young male volunteers received single doses of either 100 micrograms as a 1-minute bolus infusion or 200 micrograms orally as tablets in a controlled, randomized crossover study. In addition, 8 of the 12 subjects participated in a third treatment period in which 200 micrograms cerivastatin were administered as an oral solution as reference for determining the relative bioavailability of the tablet drug formulation. Plasma samples were analyzed for cerivastatin by a specific HPLC assay with fluorescence detection after post-column irradiation of the eluate, with a limit of quantification of 0.1 microgram/l. Following all treatments, cerivastatin was well tolerated and no clinically relevant adverse events or changes in laboratory parameters were observed. Vital signs and ECG remained unchanged. Plasma concentration/time profiles of cerivastatin following intravenous bolus could be described by a 2-compartment model with a distribution half-life of 3-5 min and an elimination half-life of 1.5-2.4 h. For the 2 oral administrations a 1-compartmental pharmacokinetic model with a first-order absorption process was best to describe the plasma concentration/time data. Based on the AUCnorm values of the 7 subjects, valid for complete pharmacokinetic evaluation, the absolute bioavailability of tablet and oral solution was 60.0 and 59.6% (90% confidence intervals 53-68%), respectively. The relative bioavailability of tablet compared with solution was 100.7% (90% confidence interval 89-114%), with tablet and oral solution showing nearly identical in vivo absorption characteristics and almost superimposable plasma concentration/time curves. The tablet formulation, therefore, can be regarded as an optimal oral formulation with respect to galenic aspects.

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form.

OBJECTIVE: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. METHODS: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. RESULTS: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. CONCLUSION: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

No interethnic differences in stereoselective disposition of oral nimodipine between Caucasian and Japanese subjects.

Using stereospecific assays plasma samples of 4 clinical-pharmacological studies have been analyzed to obtain enantioselective data on the pharmacokinetics of the calcium channel blocker nimodipine in healthy young and elderly Caucasians as well as in healthy young Japanese subjects. Basic pharmacokinetics (AUC, C(max), t(max), t1/2) and dose-proportionality based on racemic nimodipine plasma concentrations after oral single doses of 30, 60, and 90 mg were comparable in Caucasian and Japanese subjects. Stereoselective disposition of nimodipine could be observed in all cases investigated, resulting in pronounced differences in AUC and C(max) values favoring the (R)-(+)-isomer in respect of higher oral bioavailability: After single doses of 60 mg nimodipine, for instance, (R)/(S)-ratios for AUC were ranging from 5.5 - 10.0 (g.mean/SD: 7.4/1.3) in young Caucasians, for C(max) from 4.4 - 7.7 (g.mean/SD: 5.9/1.3). Corresponding ranges of 4.7 - 5.5 (g.mean/SD: 5.0/1.1) and 4.5 - 6.5 (g.mean/SD: 5.0/1.2), respectively, were calculated for Japanese subjects. The mean (R)/(S)-ratios for AUC and C(max) of all 4 studies were quite comparable between the 2 ethnic groups. The available data suggest that there are neither any differences in racemic nimodipine pharmacokinetics in Caucasians and Japanese subjects nor interethnic differences in its stereoselective disposition after oral therapeutic doses.

Investigation of nifedipine absorption in different regions of the human gastrointestinal (GI) tract after simultaneous administration of 13C- and 12C-nifedipine.

OBJECTIVE: To evaluate the absorption of nifedipine in man from four different sites of the gastrointestinal tract. METHODS: On separate occasions, nifedipine solution was administered locally to the stomach, the small intestine and two sites in the colon in 4 healthy male volunteers (age 29-34 y weight 73-82 kg, non-smokers) using a remote controlled drug delivery device (HF-capsule). In order to assess absolute and relative bioavailabilities, an intravenous infusion was given on a separate occasion and all treatments were accompanied by a simultaneous oral dose of a stable-isotope labelled nifedipine solution. This allowed to minimise the influence of intra-individual variability. Plasma samples were collected up to 24 h post dose and faeces for 72 h. A new method of analysis of nifedipine in plasma and faeces using gas chromatography with mass-selective detection (GCMS) was employed. RESULTS: Dissolved nifedipine was found to enter the systemic circulation completely along the intestine, being absorbed from jejunum to colon. Absorption was less rapid from the colon than from the upper part of the gut, but this was not associated with a decrease in absorption and/or bioavailability: Absolute bioavailability, calculated from the normalised AUC values, ranged from 42 to 56%, and bioavailability relative to oral solution was 100 to 126% (medians of the application sites). CONCLUSION: The absence of an absorption window in the intestinal tract suggests that nifedipine is well suited for use in controlled-release formulations.

Pharmacokinetic development of quinolone antibiotics.

A prerequisite for the pharmacokinetic development of quinolone antibiotics is a sensitive and accurate method for the quantification of the drug in biological fluids. Both, a drug specific (e.g. HPLC) and a drug non-specific but effect related assay (e.g. bioassay) should be used during early clinical development to detect major active metabolites. The basic pharmacokinetic behavior of the drug is investigated as part of the early phase I program, where single and multiple ascending dose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studies are performed to describe the absolute bioavailability, dose proportionality, pharmacokinetics in young and elderly, male and female volunteers. The suitability of the clinical dosage from must be evaluated in comparison to an oral solution and by quantification of the effect of food on bioavailability. The characterization of the absorption in different parts of the gastrointestinal tract may be valuable for dosage form optimization. In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine, theophylline and warfarin has to be evaluated. This can be done by in vitro and in vivo preclinical experiments, before formal clinical-pharmacology studies are performed. Further pharmacokinetic characterization (e.g. studies in special subpopulation, extended interaction studies, total recovery using 14C-labelled compound, blister fluid penetration) will be done parallel to the phase II/III development program. During these efficacy and safety trials blood samples should be obtained and PK-parameters can be calculated using sparse data analysis methods like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.

Nimodipine. Potential for drug-drug interactions in the elderly.

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

The effect of multiple oral dosing of nimodipine on glibenclamide pharmacodynamics and pharmacokinetics in elderly patients with type-2 diabetes mellitus.

Possible interactions between the calcium channel blocker nimodipine and the hypoglycemic sulphonylurea glibenclamide were investigated in patients with type-2 diabetes mellitus. These 11 patients had taken their individually adjusted antidiabetic treatment unchanged for at least 3 months and showed a satisfactory stabilization on their disease. The concomitant administration of nimodipine 30 mg t.i.d. for 6 days did not change glibenclamide pharmacokinetics as compared with the findings after glibenclamide monotherapy. The normalized AUCss,norm were 11.6 (5.0) kg x h x 1(-1) at glibenclamide monotherapy and 12.3 (5.1) kg x h x 1(-1) after combined medication, resulting in an AUC-ratio for glibenclamide of 109 (23%). Mean elimination half-lives were determined as 2.7 (0.9) h after glibenclamide alone and 3.6 (1.9) h after nimodipine comedication. There was no evidence of significant alterations in glibenclamide efficiency as seen from glucose and insulin kinetics after the simultaneous administration of glibenclamide and nimodipine (insulin Cmax, 57.0 (30.8) mU/l after glibenclamide and 64.4 (32.1) mU/l after combined treatment). Nimodipine pharmacokinetics under nimodipine and glibenclamide steady-state conditions were similar to findings in literature: AUCss,norm 0.10 (0.04) microgram x h x 1(-1), Css,max 20.7 (8.3) microgram x 1(-1). Hemodynamics, clinical chemistry and tolerance did not differ during both treatments. Thus, a clinically relevant drug interaction between nimodipine 30 mg t.i.d. and glibenclamide during long-term treatment can be excluded.

Determination of the enantiomers of nisoldipine in human plasma using high-performance liquid chromatography on a chiral stationary phase and gas chromatography with mass-selective detection.

A method is described that combines chiral HPLC and off-line GC with mass-selective detection for the quantitation of the enantiomers of nisoldipine [(+/-)-I] in human plasma. An isotope-labelled internal standard [nine-fold deuterated (+/-)-I] is used throughout the assay. The limit of quantification is 0.1 microgram/l for each enantiomer. Data on the precision, accuracy and selectivity of the method are presented. Enantioselective analysis was performed in subjects receiving the racemic drug in tablet form. In healthy volunteers the maximum concentration and the area under the curve of the pharmacologically more active (+)-enantiomer were greater by 9-fold and 13-fold, respectively, compared to those of the (-)-enantiomer. In elderly hypertensive patients plasma concentrations of (+)-I were ca. five times as high as those of the (-)-enantiomer. Stereoselectivity was not affected by hepatic impairment. After intravenous administration of (+/-)-I there were no relevant differences between the plasma concentrations of the enantiomers.

A comparison of the pharmacokinetics of nisoldipine in elderly and young subjects.

Nine young and 12 elderly healthy volunteers received nisoldipine 10 mg once a day for 7 days. Plasma nisoldipine concentrations were measured on Day 1 and on Day 7. Higher plasma drug concentrations were observed in the elderly group than in the young group with the values for AUC being approximately doubled in the elderly group. There was no evidence of significant accumulation in either age group.

Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man.

Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (-15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r = 0.92, nitrendipine r = 0.80 and nisoldipine r = 0.79. Nimodipine showed no such correlation.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of nisoldipine. III. Biotransformation of nisoldipine in rat, dog, monkey, and man.

After intraduodenal administration of 14C-labelled (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) to rats approx. 68% of the dose was excreted in the bile in the first 6 h. In an isolated perfused rat liver model the excretion with the bile was 56% of the total dose within 3 h. The recovery of radioactivity from orally administered [14C] nisoldipine was approx. 32% (rat), 23% (dog), 73% (monkey) and 74% (man), resp., in the urine. The unchanged drug was neither detected in the urine nor in the bile, but nisoldipine was present in plasma of the rat 30 min after dosing and up to 24 h in man. The drug was extensively metabolized: 18 biotransformation products were identified by comparison with synthetic reference compounds using combined GC-MS, 1 NMR-spectroscopy, mass spectrometry, gas chromatography/radio-gas chromatography and two-dimensional thin layer chromatography, 6 of them being quantitatively important (about 80% of the radioactivity excreted in urine). The metabolites identified accounted for approx. 82% (rat: bile and urine), 19% (dog, due to the low renal excretion), 58% (monkey: urine) and 64% (man: urine) of the excreted dose, resp. The following biotransformation steps occurred: hydroxylation of the isobutyl moiety, dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, hydroxylation of one of the methyl groups in 2- or 6-position and subsequent oxidation to the carboxylic acid, oxidation of one of the methyl groups of the isobutyl moiety to the carboxyl group reduction of the aromatic nitro group (minor biotransformation reaction) and glucuronidation as phase II reaction.

Pharmacokinetics of nisoldipine in renal dysfunction.

The pharmacokinetics of nisoldipine have been studied after oral administration of one 10 mg tablet to 3 groups of patients: Group A (n = 8) with a mean creatinine of 90 ml/min, Group B (n = 8) with a mean creatinine clearance of 12 ml/min and Group C of 12 patients on maintenance haemodialysis. All of them were studied off-dialysis and 7 were also studied on a dialysis day. No significant differences were observed between Groups A, B and C (on an interdialysis day) in AUC (0-7h), tmax, Cmax and plasma protein binding. Unchanged nisoldipine could not be recovered from the urine in any patient. Haemodialysis did not significantly affect AUC, tmax and Cmax, and nisoldipine could not be detected in the dialysate. The results indicate that the dose of nisoldipine need not be changed in patients with renal dysfunction, and that a supplementary dose is not required after haemodialysis. Blood pressure in the uraemics fell more than in the patients with good renal function.