Comparison of the pharmacokinetics of two nicotine transdermal systems: nicoderm and habitrol.

This randomized, crossover study compared the nicotine and cotinine pharmacokinetic parameters and plasma concentration profiles of two different nicotine transdermal products: Nicoderm (Alza, Palo Alto, CA; and Marion Merrell Dow, Kansas City, MO) and Habitrol (Basel Pharmaceuticals, Summit, NJ). The two treatments were randomly assigned to each of 24 male smokers and worn for 24 hours each day for 5 days, with a 6-day washout between treatments. Plasma nicotine and cotinine concentrations were measured on day 1 and day 5 of each treatment. Mean delivered dose differed significantly between products, and the two products were not bioequivalent. The Nicoderm system provided higher mean plasma nicotine concentrations, particularly during the first 8 hours after system application. The mean steady state Cmax, AUC, and degree of fluctuation (DF) values were significantly greater for the Nicoderm system than for Habitrol. The mean nicotine tmax value for the Nicoderm system was significantly shorter (P < .001) than that for Habitrol (2.7 versus 8.6 hours). Steady state cotinine AUC values and plasma concentrations were significantly lower for Habitrol than for the Nicoderm system. The incidence of adverse events was similar for both products.

Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers.

The pharmacokinetics of vigabatrin were investigated after single and multiple oral doses in two groups of 24 healthy male volunteers. Vigabatrin was well tolerated by the volunteers; headache was the most frequently reported adverse event. There were no clinically remarkable changes in serum chemistry, urinalysis, or hematology attributable to vigabatrin. For the single-dose study, a stepwise linear contrast method was used to assess dose proportionality. The results showed that vigabatrin exhibited dose linear pharmacokinetics after single oral doses ranging from 0.5 to 4.0 g. Slight changes in the terminal phase half-life and renal clearance were evident in the higher dosage groups. These changes with increasing dose of vigabatrin were relatively minor and not considered to be clinically important. Evaluation of the multiple-dose pharmacokinetics indicated that vigabatrin exhibited dose linearity over the range of 0.5 to 2.0 g administered every 12 hours. The terminal phase half-life and renal clearance of vigabatrin during multiple dosing were consistent with that after single doses. During multiple dosing, steady-state concentrations of vigabatrin were reached on the second day of dosing, and drug accumulation was minimal.

Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation.

The antihistaminic drug terfenadine, alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (Seldane), is of interest because of its lack of sedative properties. Major routes of metabolism include oxidative N-dealkylation to 4-(hydroxydiphenylmethyl)-piperidine (1) and oxidation of a tert-butyl methyl group to a primary alcohol (2), which is subsequently oxidized to a carboxylic acid. Rates of formation of 1 and 2 varied approximately 30-fold in the 17 human liver microsomal samples examined and were highly correlated with each other, suggesting that the same enzyme may be involved in both oxidations. The rates of formation of 1 and 2 were both correlated with rates of nifedipine oxidation (a marker of cytochrome P-450 (P-450) 3A4) but not with markers for other human P-450s. Microsomal oxidation of (both enantiomers of) terfenadine to 1 and 2 was markedly inhibited by gestodene, a selective mechanism-based inactivator of P-450 3A enzymes but not by any of several other P-450 inhibitors. Antibodies raised against P-450 3A4 could inhibit most of the oxidation of (both enantiomers of) terfenadine to 1 and 2 in a microsomal sample having high catalytic activity but antibodies recognizing other P-450s had no effect. The oxidation of terfenadine to 1 and 2 was catalyzed by purified human liver microsomal P-450 3A4 and by partially purified yeast recombinant P-450 3A4. These results provide evidence that P-450 3A4 (and possibly other P-450 3A enzymes) play a major role in the oxidation of (both enantiomers of) terfenadine to both of its major oxidation products.(ABSTRACT TRUNCATED AT 250 WORDS)

Single- and multiple-dose pharmacokinetics of Nicoderm (Nicotine Transdermal System).

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half-life (t1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady-state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady-state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t1/2 did not change compared with single application. The mean ratios of cotinine-to-nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated.

Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites.

Drug absorption through the skin can vary according to the application site. The nicotine transdermal system, Nicoderm (Alza Corp., Palo Alto, CA) contains a rate-controlling membrane designed to regulate delivery of nicotine to the skin and thus limit variability in nicotine plasma levels. Plasma nicotine concentrations were compared after application of NTS 14 mg/day to three different skin sites (upper back, upper outer arm, upper chest) in a randomized, crossover study involving 12 healthy male smokers. Plasma nicotine profiles from all three sites were similar: nicotine concentrations increased rapidly within 2 to 4 hours, reached broad peaks of approximately 11 to 14 ng/mL, and then remained relatively constant between 8 and 24 hours after application. The mean nicotine maximum peak plasma concentration values for nicotine transdermal system application to the arm, back, and chest were equivalent (13.8, 14.6, and 13.2 ng/mL, respectively). The mean time to reach peak concentration (tmax) (3 to 6 hours), and area under the curve (168, 186, and 183 ng.h/mL) values for the arm, back, and chest, respectively, were not significantly different. Thus, bioequivalent plasma nicotine concentrations were achieved irrespective of the application site on the upper body.

Absence of food effects on the pharmacokinetics of terfenadine.

Administration of terfenadine (Seldane) immediately after a high fat breakfast slightly affects the rate but not the extent of absorption relative to fasting administration. Mean peak levels of the active metabolite were increased by 13 per cent but delayed by 0.9 h while AUC was virtually the same as when terfenadine was administered while fasting. Changes in rate of absorption may be due to delayed gastric emptying and more rapid terfenadine solubilization. In any case, these rate differences are unlikely to be clinically important in the absence of differences in extent of absorption.

Pharmacokinetics of terfenadine in healthy elderly subjects.

The pharmacokinetics of the terfenadine active metabolite, metabolite I, was examined in ten healthy elderly adults and ten younger adults after single-dose oral administration of 120-mg terfenadine. All subjects successfully completed the study without reporting sedation or other adverse events. Absorption was rapid in both the young and elderly. The mean Cmax was the same for both groups, 501 ng/mL, and occurred at 2.3 hours in the young subjects and 2.5 hours in elderly subjects. However, the apparent clearance was reduced by about 25% in the elderly. After correcting clearance for bodyweight, this difference was not statistically significant.

Direct enantiomeric separation of terfenadine and its major acid metabolite by high-performance liquid chromatography, and the lack of stereoselective terfenadine enantiomer biotransformation in man.

Direct enantiomeric separation of terfenadine and its major acid metabolite was achieved by using two different chiral stationary phase columns with two different mobile phase systems. Further, the enantiomeric composition of the human urinary acid metabolite has been determined, indicating a non-stereoselective biotransformation in man.

Clinical pharmacology of intravenous enoximone: pharmacodynamics and pharmacokinetics in patients with heart failure.

Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to IV) received a 24-hour infusion of enoximone followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I to III received an 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0, or 10.0 micrograms/kg/min. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/min without a loading dose. Serial assessment of hemodynamics, plasma levels of enoximone and enoximone sulfoxide, and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index, and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate, and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate, and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg, the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 micrograms/kg/min), rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in guiding the intravenous administration of enoximone.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of terfenadine and terfenadine acid metabolite in plasma using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

This work describes the methodology for the analysis of terfenadine and the acid metabolite of terfenadine in plasma using high-performance liquid chromatography. The use of solid-phase extraction allows the use of robotic or manual sample preparation for the efficient clean-up of terfenadine and terfenadine acid metabolite from plasma. Additional selectivity is obtained through the use of fluorescence detection. For terfenadine, the validated quantitation range of this method is 10.0-84.2 ng/ml with coefficients of variation of 5.7-30%. For terfenadine acid metabolite, the validated quantitation range of this method is 8.2-500 ng/ml with coefficients of variation of 4.1-24%.

Determination of the metabolites of terfenadine in human urine by thermospray liquid chromatography-mass spectrometry.

Thermospray liquid chromatography-mass spectrometry (TSP LC-MS) was used to determine human urinary metabolites of terfenadine after oral administration of terfenadine tablets. In addition to the two previously identified major metabolites, azacyclonol (MDL 4829) and the 'acid' metabolite (MDL 16,455), three additional metabolites were also detected. One of the additional metabolites was identified as the 'alcohol' metabolite (MDL 17,523) and the other two were proposed to be an 'aldehyde' and a 'ketone-acid' metabolites from their TSP mass spectra. The results of this study demonstrated that TSP LC-MS is a useful technique for the study of terfenadine biotransformation.

Pharmacology and pharmacokinetics of enoximone.

Enoximone is an inotropic vasodilating agent. Its principal effects are positive inotropism and vasodilation, which are not accompanied by changes in myocardial oxygen consumption. An inotropic dose of enoximone increases the level of cyclic AMP in the isolated, blood-perfused dog papillary muscle owing to its selective inhibition of the one isoform of cyclic AMP phosphodiesterase from the dog heart that is inhibited by cyclic GMP. Studies on the metabolism and pharmacokinetic profile of enoximone have been carried out in the rat, dog and monkey. Enoximone is metabolized mainly by oxidation to enoximone sulphoxide in all species studied, and this is reversible. In congestive heart failure patients, approximately 74% of a rapidly administered intravenous dose of enoximone is excreted in a 24-hour urine collection as the sulphoxide metabolite; only about 0.49% is recoverable as intact drug. Enoximone sulphoxide has the same inotropic and vasodilator activities as enoximone but is 0.13-0.14 times as potent and has a 13 times longer duration of inotropic action in the dog. It is suggested that the metabolite may contribute to some of the effects that follow enoximone administration.

Human serum and plasma protein binding of enoximone and its sulfoxide metabolite.

Experimental factors and determinants of the protein binding of enoximone (a new cardiotonic agent) were investigated in human serum from healthy, drug-free subjects using a rapid ultrafiltration method; these factors and determinants included nonspecific binding to the apparatus, ultrafiltrate volume, temperature, serum pH, enoximone serum concentration, and enoximone sulfoxide (metabolite) concentration. It was demonstrated from mass balance experiments that nonspecific binding to the apparatus did not occur. Within the range investigated, ultrafiltrate volume did not affect the binding result. However, serum pH and temperature were critical variables. At pH 7.4 and 37 degrees C, enoximone serum binding occurred to the extent of approximately 70%; over the therapeutic serum concentration range, this binding was concentration independent. Experiments with purified albumin solutions indicated that much of the serum binding could be accounted for by albumin. At concentrations exceeding those observed clinically, enoximone sulfoxide did not affect enoximone serum binding. In another experiment, enoximone binding to serum was compared with that from plasma containing either heparin or disodium EDTA. There were essentially no differences. Enoximone sulfoxide serum protein binding was also investigated in serum from healthy, drug-free human subjects; binding occurred to the extent of approximately 5%.

Biotransformation and pharmacokinetic overview of enoximone and its sulfoxide metabolite.

Enoximone possesses both positive inotropic and vasodilatory activities and may be useful in the treatment of patients with congestive heart failure (CHF). In all animal species investigated (rat, dog, monkey and man), the major urinary metabolite is the sulfide oxidation product (sulfoxide); very little unchanged drug appears in urine. Both in vitro and in vivo animal studies indicate reversibility of the sulfoxidation reaction; therefore, it is presumed that sulfoxidation is reversible in man. In normal healthy subjects, no difference in extent of absorption due to dietary state is observed. In patients with New York Heart Association class III to IV CHF, median terminal disposition half-lives for enoximone and its sulfoxide metabolite are 6.2 to 7.6 hours, respectively. Enoximone and sulfoxide plasma concentrations from high dose intravenous infusion studies in patients with class III to IV CHF were also investigated. The collective data suggest nonlinearity in one or more pharmacokinetic processes, of which one may be saturation of sulfoxidation. No direct relation between enoximone and/or the sulfoxide metabolite plasma concentration and pharmacologic effect has been established.

Acute hemodynamic effect of oral MDL 17,043 in severe congestive heart failure.

MDL 17,043, when administered intravenously in humans, produces a significant and salutary hemodynamic response. To determine its acute effect when administered orally (3 mg/kg), 10 patients with severe congestive heart failure were studied by right-sided cardiac catheterization for 8 hours. At 4 hours after drug ingestion, there was significant improvement in several hemodynamic measurements. Cardiac index increased 38% over baseline (from 1.9 +/- 0.4 to 2.6 +/- 0.4 liters/min/m2, p less than 0.01), arteriovenous oxygen difference decreased by 30% (from 8.0 +/- 1.4 to 5.6 +/- 1.2 vol%, p less than 0.01), heart rate increased by 8% (from 85 +/- 16 to 92 +/- 16 beats/min, p less than 0.05), stroke volume index increased by 22% (from 23 +/- 5 to 28 +/- 4 ml/beat/m2, p less than 0.05), left ventricular stroke work increased by 24% (from 18 +/- 5 to 22 +/- 5 g-m/m2, p less than 0.01), mean arterial pressure decreased by 10% (from 79 +/- 6 to 71 +/- 9 mm Hg, p less than 0.01), mean right atrial pressure decreased by 40% (from 10 +/- 5 to 6 +/- 4 mm Hg, p less than 0.01), and mean pulmonary artery wedge pressure decreased by 36% (from 22 +/- 5 to 14 +/- 6 mm Hg, p less than 0.01). Cardiac index, arteriovenous oxygen difference, mean arterial pressure, right atrial pressure, and pulmonary artery wedge pressure remained significantly improved at 8 hours. These findings indicate that MDL 17,043 is active when administered orally and produces beneficial hemodynamic effects for as long as 8 hours.

Dose related induction of the drug metabolizing enzymes of rat liver by cilobamine.

Cilobamine , an antidepressant, was investigated for its influence on the hepatic drug metabolizing enzymes ( DME ) of male Charles River CD rats. Cilobamine doses (3, 10, 30, 100, and 300 mg/kg po, as free base) were compared to sodium phenobarbital (PB) doses (3, 10, 30, 100, and 200 mg/kg po, as free acid). Compounds were given daily for 4 days and all tests were done on Day 5. Ethylmorphine n-demethylase, aniline hydroxylase, microsomal cytochrome P-450 content, relative liver weight, and recoverable microsomal protein were quantitated. The results indicated that cilobamine was an inducer of the DME but not as potent as PB. Cilobamine did not exert any inductive responses at 3 mg/kg. At 10 and 30 mg/kg some but not all test systems were increased. However, at 100 and 300 mg/kg all were increased. PB increased all systems at all doses studied. Electron micrographs of livers of rats given 100 mg/kg of cilobamine or PB revealed hypertrophy of the smooth endoplasmic reticulum. The time course of induction in rats given 100 mg/kg po showed that responses in the cilobamine rats peaked after the second dose and plateaued with later doses. Responses in PB rats increased markedly after one dose and showed a continual increase with later doses. Induction of the DME was also demonstrated in female rats.

Simultaneous analysis of a new cardiotonic agent, MDL 17,043, and its major sulfoxide metabolite in plasma by high-performance liquid chromatography.

MDL 17,043 or 1,3-dihydro-4-methyl-5-[4-(methylthio)benzoyl]-2H-imidazol-2-one, is a new cardiotonic agent being developed for the treatment of congestive heart failure. This communication describes a sensitive and selective analytical procedure for the simultaneous analysis of MDL 17,043 and its major oxidative metabolite in plasma. The method involves addition of internal standard and organic solvent extraction, followed by separation with high-performance liquid chromatography and detection by ultraviolet absorption. The assay has good precision and accuracy. Evidence for the positive identification of the sulfoxide metabolite is also presented.