Food effect on the oral bioavailability of Manidipine: single dose, randomized, crossover study in healthy male subjects.

The effect of food on the oral bioavailability of a manidipine 20 mg tablet was studied after a single administration in 12 male healthy subjects. The clinical trial was conducted as an open, randomised, crossover study. In two different administration sessions, the subjects received a 20 mg manidipine tablet either in the fasting state or after a standardized breakfast. Plasma samples were collected before and at different times after each administration for up to 24 h. The concentrations of manidipine and its pyridine metabolite (M-XIII metabolite) were determined by HPLC with coulometric detection. The tolerability of manidipine was good. Only two cases of mild headache, one with each treatment, were reported. Food significantly improved the absorption, with an increase in AUC from 19.1 to 27.2 ng.h/ml (geometric mean, p<0.01) but did not modify the rate of absorption (tmax unchanged, median = 1.5 h). Peak plasma concentration was also increased (from 6.2 to 7.8 ng/ml), but the difference was not statistically significant (p=0.18). Other pharmacokinetic parameters (apparent elimination half-life and mean residence time) remained unchanged. The increase in bioavailability of manidipine administered with food is related to its high lipophilicity and may be explained through a solubilization effect produced by food and bile secretions.

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.

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.

Diffusion of oral ofloxacin (HOE 280) into human prostatic tissue: assessment by an improved high-performance liquid chromatographic method.

11 patients with a prostatic adenoma received a single oral 200 mg dose of ofloxacin 2 h before transurethral resection of the prostate. During the operation, blood samples and prostatic tissue cuttings were collected simultaneously. Ofloxacin was assayed by an original HPLC method with UV detection. The mean concentration of the unchanged drug was 5.10 mg/kg wet tissue and 1.81 mg/l in prostatic tissue and plasma, respectively. The 3.17 prostate/plasma ratio reflected a good penetration of ofloxacin into the prostatic tissue.