Pharmacokinetic profile of 14C-labeled clopidogrel.

In order to obtain a global assessment of circulating clopidogrel-related products and of the excretion of the drug, the pharmacokinetic behavior and the excretion balance of 14C radioactivity following the administration of a single dose of 75 mg of 14C-labeled clopidogrel were compared in 6 clopidogrel-free healthy male subjects (Period I) and after 7 days of once daily therapy with the unlabeled drug in these subjects (at steady state) (Period II). The two study periods were separated by a 4-week washout period. For each administration of 14C-clopidogrel, blood samples were collected before and at regular intervals over 28 days after administration of the radiolabeled drug. Expired air samples were collected before and over 24 hours after the administrations of 14C-clopidogrel. All urine voided and all stools were collected before and for up to 120 hours after the administration of 14C-clopidogrel, in consecutive periods of 12 to 24 hours. The mean radiocarbon plasma concentration profiles after administration of 14C-clopidogrel given as a single dose (Period I) and during steady state (Period II) were superimposable. There were no statistically significant differences between the two treatments for any parameters. A Cmax of 3.9 mg-Eqv/L was reached after a median time of 1 hour (Tmax). The plasma elimination half-life, t1/2, ranged from 336 hours to 672 hours in Period I and from 275 to 433 hours in Period II. The radiocarbon excretion over 10 to 12 hours post-dose (time to last measurable radioactivity) in expired air represented 0.31 to 0.35% of the administered dose. Mean cumulative urinary excretion over 120 hours represented 41% of the dose after a single-dose administration and 46 % after administration at steady state. The cumulative fecal recovery over 120 hours ranged from 35 to 57% of the dose in Period I and from 39 to 59% of the dose in Period II. Mean total excretion of radioactivity was 92% of the dose during Period I and 93% during Period II. These data indicate that, following multiple-dose administration of clopidogrel, the biodisposition of the drug remains unaltered compared to a single dose.

Single dose pharmacokinetics of manidipine in hepatic impaired patients and healthy controls.

The pharmacokinetics and safety of a single oral dose of 20 mg manidipine dihydrochloride have been studied in 8 patients with mild to moderate hepatic impairment (grade A or B in Child's classification, or score < or = 7 in Pugh's modification of Child's classification), and in 12 healthy subjects. They received one 20 mg manidipine dihydrochloride tablet with 100 ml of tap water after a standard breakfast. Manidipine was determined using HPLC with electrochemical detection from plasma samples taken up to 24 or 36 h after dosing. The medication was well tolerated. A trend toward higher Cmax, AUC, and MRT was observed in patients with a more severe hepatic impairment, as a consequence of reduction in the liver metabolic function. Patients with grade A hepatic impairment did not exhibit significantly altered pharmacokinetics with respect to healthy subjects, while grade B impairment patients had significantly higher AUC and MRT. Tmax values pointed to reduced absorption rate in patients compared to healthy subjects; the changes were more evident in grade B than grade A patients, although statistical significance was not reached. The reduction in absorption rate in grade B patients is probably related to their higher mean age, since this effect has been reported for manidipine. The pharmacokinetics of manidipine seem only modified in patients with a certain degree of hepatic impairment (at least Pugh grade 6 and Child grade B); therefore, adaptation of the dosing regimen does not seem to be generally recommendable, but should be modulated according to the liver status of the patient.

Pharmacokinetics of nitazoxanide after single oral dose administration in 6 healthy volunteers.

The objective of this study was to gather first information on the time course of plasma concentrations and urinary excretion of the antiprotozoal nitazoxanide (N) and to identify potential metabolites in healthy subjects after a single oral dose of 500 mg of nitazoxanide. The clinical trial was conducted as an open single oral dose study in 6 healthy male subjects. After a standardized continental breakfast the subjects took a single oral dose of 500 mg nitazoxanide (coated tablet) with 100 ml tap water. The plasma concentration and the urinary excretion of nitazoxanide (N), desacetyl-nitazoxanide (DN), aminonitrothiazole (ANT), acetylsalicylate (AS), salicylate (S), gentisate (G) and salicylurate (SU) were monitored up to 72 h after administration. The only measurable species in plasma was DN, which reached a Cmax of 1.9 mg/l (range 1.1-2.5) 2-6 h after dosing, and an AUC of 3.9-11.3 mg x h/l. Its terminal half-life ranged from 1.03 to 1.6 h. DN was extensively bound to plasma proteins (> 97.5%). Only 8% of the dose was recovered in the urine, in the form of DN (5%), SU (3%), and traces of ANT (0.1%). In vitro N was very rapidly hydrolyzed to DN by plasma esterases.

Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy volunteers.

The bioavailability patterns of a 100 mg metoprolol controlled release tablet and a 10 mg bisoprolol normal release tablet were compared in a single dose crossover study in 12 healthy subjects. The plasma drug concentration levels were measured for 36 h post-dose, using HPLC with fluorimetric detection. The 2 formulations were equally well tolerated, headache being the most frequently reported adverse event. Episodes of bradycardia (heart rate < 50 bpm) occurred at a similar rate with both formulations. The plasma metoprolol profile differed significantly (p < 0.05) from the bisoprolol profile regarding time to maximum concentration, mean residence time, the ratio of peak concentration (Cmax) to the area under the curve (AUC) and the plateau time as estimated from the half-value duration. The average drug plasma concentration observed 24 h after administration still accounted for 54% of the Cmax value for the metoprolol controlled release tablet, but only 23% with the bisoprolol normal release tablet. A large inter-individual variability was seen in the bioavailability of metoprolol, with 3 subjects (characterised as CYP2D6 deficient) exhibiting AUC values 8 - 10 times larger than in the other subjects. The controlled release pattern of the formulation was similar in slow and fast metabolizers. No such variability pattern was apparent for bisoprolol. The findings allow to conclude that, after administration of the metoprolol controlled release tablet, the rate of absorption of the active principle is significantly slower, therefore yielding more constant plasma concentration levels over the 24 h post-dose period, than after administration of the bisoprolol normal release tablet.

Relative bioavailability of carbinoxamine and phenylephrine from a retard capsule after single and repeated dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylephrine (PE, CAS 59-42-7) after single dose administration of a retard capsule (Rhinopront) containing 20 mg PE hydrochloride and 4 mg CA maleate, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects according to a standard crossover design with a one-week wash-out. The pharmacokinetic profile of the active ingredients of the retard capsule was also investigated in the same subjects under repeated dosing conditions (one capsule b.i.d. during 4 days). Blood samples were collected before each administration and up to 36 h after the first and last doses. CA and total PE (free + conjugated) were assayed in the plasma samples by HPLC with coulometric detection and by gas chromatography with electron-capture detection, respectively. The pharmacokinetic parameters obtained after single dose administration indicated an effective slow release of PE and CA with the retard capsule, compared to the solution. Significantly dampened Cmax, delayed tmax and prolonged plateau time were observed. Despite the clear decrease in absorption rate, the two formulations yielded a similar extent of absorption for CA (90% confidence interval of AUC ratio: 61-111%), but not for PE (90% confidence interval of AUC ratio: 56-69%). At steady-state, accumulation of the two active principles apparently followed simple superposition (accumulation index R = 1.6 for PE and 3.9 for CA). The slow absorption pattern of the formulation was maintained at steady-state with tmax and plateau time similar to single dose conditions.

Oral bioavailability of CHF1194, an inclusion complex of piroxicam and beta-cyclodextrin, in healthy subjects under single dose and steady-state conditions.

CHF1194 is an inclusion complex of beta-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, beta-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-beta-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of beta-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5'-hydroxypiroxicam and beta-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80-125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5'-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with beta-cyclodextrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Exploratory study of the decongestive effect of Rhinopront syrup in adults and in children with acute rhinitis.

The decongestive effect of Rhinopront syrup was assessed in 18 adults and 18 children with acute rhinitis, by comparison to a matching placebo syrup and to a commercial standard decongestant (Triaminic tablets or drops). The evolution of symptoms following single dose administration of each treatment was estimated both by objective measurements of nasal resistance using bilateral rhinomanometry and by subjective evaluation of nasal congestion and aspect of the mucosa. In children, the treatment was continued over the next 4 days and the global clinical efficacy of the formulations was subjectively evaluated by the parents. In adult patients, a significant decrease in nasal resistance was obtained after a single dose of Rhinopront (15 g). The effect was already important after 0.5 h and reached a minimum of approximately 50% of baseline within 1 to 2 h; the drop in nasal resistance was significantly less intense for Triaminic (p < 0.05; 0.5-1-h period) and for the placebo (p < 0.05; 0.5-2-h period). In children, the scatter of rhinomanometric measurements precluded the observation of any significant within- or between-group differences; however, a significantly lower nasal congestion score was observed for Rhinopront than placebo, between 4 and 10 h after single dose administration (1 g per year of age). The present work suggests that Rhinopront is an effective nasal decongestant in adults and children with acute congestive rhinitis and supports the adequacy of the proposed twice-daily dosing rate.

Pharmacokinetics of brodimoprim in special populations.

The pharmacokinetics of brodimoprim have been investigated after single oral dose administration in children, in healthy adults, and elderly subjects, as well as in patients with mild renal failure (creatinine clearance 40-70 mL/min) or liver insufficiency (Child-Pugh grade A or B). The plasma half-life increased moderately with age. The percent brodimoprim bound to plasma proteins, 93%, was identical in renally impaired patients and in healthy controls but decreased to 90% or less in liver insufficiency. The apparent distribution volume and clearance were much higher in children than in adults. Urinary excretion of unchanged brodimoprim amounted to 5-10% of the administered dose. The steady-state pharmacokinetics of brodimoprim has also been investigated in elderly subjects (400 mg loading dose followed by 7 days 200 mg once daily). There was no significant modification of elimination half-life and of clearance upon repeated dosing. Renal excretion of brodimoprim and hydroxy metabolite at steady-state reached 9% and 14% per 24 hours in the elderly, compared to 9% and 24% in young adults. The accumulation factor reached 3.3 +/- 0.4 and 2.7 +/- 0.3 respectively.

Relative bioavailability of carbinoxamine and phenylpropanolamine from a retard suspension after single dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylpropanolamine (PP, CAS 14838-15-4) after single dose administration of a retard suspension (Rhinopront), containing a resinate as sustained-release agent, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects who received the two formulations according to a standard crossover design with a one-week wash-out. Blood samples were obtained up to 24 h post-dose. PP and CA were assayed in the plasma samples by gas chromatography with electron-capture detection and HPLC with coulometric detection, respectively. The pharmacokinetic results indicated sustained release of the two active principles with the retard suspension: CA appeared in plasma at a much slower rate than with the solution, a 30% lower Cmax being reached after 8.0 h instead of 3.0 h post-dose. For PP, Cmax was 23% lower and occurred 3.0 post-dose instead of 1.5 h with the solution. The extent of absorption of the two drugs, as assessed by AUC (0-24 h), was slightly smaller with the retard suspension than with the aqueous solution. However, the test/reference ratio remained within 95% confidence intervals of 80-87% and 88-98% for CA and PP, respectively, indicating bioequivalence of the two formulations. A simulation of the plasma levels during repeated administration indicated that dosing with the retard suspension at 12-h intervals should yield the same steady-state plasma levels as a 5 times daily administration of a divided dose of the aqueous solution, for both drugs.

Compartmental analysis of steady-state taurocholate transport kinetics by isolated rat hepatocytes.

We used compartmental modeling to describe taurocholate transport by isolated rat liver cells in suspension. Cells are preincubated in the presence of unlabeled taurocholate. When a steady-state for taurocholate is reached, radiolabeled taurocholate is added to the medium and its exchange kinetics between the medium and the cells are followed over time. Because the studies are performed under steady-state conditions, the kinetics can be described by linear compartmental models. We found a closed two-compartment model sufficient to describe the steady-state transport data. Simulations reveal that if the pools of free and bound intracellular taurocholate exchange rapidly, the cells will behave as a single, kinetically homogeneous compartment and intracellular events will not influence the exchange kinetics of taurocholate between the medium and the cells. The two-compartment model was used to study the concentration dependence of taurocholate transport by isolated cells. Steady-state transport rates and taurocholate concentrations in the medium and the cells were calculated using the model equations. Taurocholate influx, accumulation and efflux processes were studied simultaneously by examining the relationship between appropriate combinations of these variables. Application of this approach to study the inhibition of taurocholate transport by taurochenodeoxycholate is illustrated. In conclusion, this method provides a complementary approach to initial rate studies, which are generally used to investigate bile acid transport by isolated cells.

Saturation of hepatic transport of taurocholate in rats in vivo.

A single intravenous injection of [14C]taurocholate was followed up in blood and bile of rats submitted to steady intravenous infusions of taurocholate (TC) at rates of 0.0, 0.5, 1.0, and 1.5 mumol.min-1.100 g body wt-1 for at least 30 min. The transport rate constants and the amounts of TC in different compartments were estimated by weighted least-squares adjustment of a six-compartment model to the experimental data (3 compartments for TC distribution in blood, 2 compartments for liver, and 1 compartment for sinusoidal blood space). The saturation of the TC excretion rate was reached at 0.8 mumol.min-1.100 g body wt-1. It was characterized by a decrease of both the uptake and excretion rate constants, by an increase of the ratio of the amounts of TC in the two intrahepatic compartments (H'/H), and by an intrahepatic TC concentration of approximately 2 mM. When tauroursodeoxycholate (TUDC) was infused at a rate of 0.5 mumol.min-1.100 g body wt-1 together with TC at a rate of 1.5 mumol.min-1.100 g body wt-1, the TC excretion rate increased to 1.2 mumol.min-1.100 g body wt-1, and the excretion rate constant and H'/H decreased toward control values. These results support the hypothesis that the saturation of the transport of TC is due to TC hepatotoxicity and can be reduced by TUDC. Michaelis-Menten parameters, derived from saturation curves for both uptake and excretion steps, closely matched earlier results, thus confirming the good descriptive capacity of the model.

Compartmental modeling of the hepatic transport of taurocholate in the rat in vivo.

Compartmental analysis was used to study the hepatobiliary transport of taurocholate (TC) in the rat in vivo. The available data are the following: [14C]TC kinetics in blood and bile, weighting factors associated with these data and computed from a theoretical variability model, and TC excretion rate in bile. The lumped model that best fits the data contains five compartments: three compartments for TC distribution in blood and two compartments for the liver. It includes a compartmental representation of the laminar flow of bile in the collecting catheter. This model overestimates TC concentration in blood. A perfusion model that includes a compartment representing explicitly the sinusoidal TC concentration gradient was developed. TC concentration in blood estimated by this model is in good agreement with direct measurements, showing that the perfused model has a better descriptive capacity than the lumped model. The amounts of TC estimated in the two hepatic compartments are similar to values previously published.