Pharmacokinetics and tissue penetration of fluconazole in humans.

The pharmacokinetics and tissue/fluid penetration of fluconazole have been studied in more than 400 healthy individuals and various subsets of patients. The pharmacokinetics of fluconazole are similar following intravenous and oral dosing. Oral bioavailability is greater than 90%, and concentrations peak approximately 2 hours after dosing. The apparent volume of distribution is 0.7 L/kg, and plasma protein binding is low (12%). The drug is metabolically stable, with renal excretion accounting for approximately 80% of the elimination as unchanged drug. Repeated once-daily dosing results in an increase in plasma levels of approximately 2.5-fold, with steady state achieved by day 7. Plasma levels are dose-proportional, and the elimination rate remains constant across the dosage range and over time. The plasma half-life of fluconazole is approximately 30 hours. The pharmacokinetics are similar in healthy young adults and in the elderly, but dose modification is required in patients with renal impairment. Fluconazole diffuses readily into the cerebrospinal fluid, sputum, and saliva and is concentrated in the urine and skin.

Absorption of amlodipine unaffected by food. Solid dose equivalent to solution dose.

The oral bioavailability of amlodipine in healthy volunteers was compared in two separate studies after solution and capsule doses, and after capsule doses in fed and fasting states. The bioavailability of amlodipine was equivalent both in terms of rate and in extent of absorption between solution and capsule doses and in the fed and fasting states.

A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects.

The potential use of calcium antagonists in the treatment of hypertension and ischemic heart disease in elderly patients creates a requirement for pharmacokinetic information that is specific for that age group. This study describes the pharmacokinetics of amlodipine after single oral doses of 5 mg in 16 elderly subjects, mean age 72 years, age range 65-85 years. The principal findings were that the mean elimination half-life was 48 h and that peak plasma drug concentrations were not observed until 7 h after dosing. In comparison with data obtained from a group of young subjects, mean age 26 years, there were significant differences in pharmacokinetics. The terminal elimination half-life of 48 h in the elderly was significantly longer than that of 35 h in the young subjects and there was a correspondingly greater area under the curve in the elderly, by approximately 50%. These findings are consistent with an age-related reduction in drug clearance.

The pharmacokinetics and pharmacodynamics of doxazosin compared with atenolol during long-term double-blind treatment.

The pharmacodynamics of doxazosin and atenolol were compared on single study days in 39 patients with mild to moderate hypertension receiving long-term double-blind treatment. The pharmacokinetics of doxazosin were investigated in the 20 patients receiving doxazosin. Individually titrated once daily doses of doxazosin were 1, 2, 4, 8 or 16 mg and of atenolol 50 or 100 mg. Patients were first investigated after at least one month on constant dose and then again after at least a further three months. Mean plasma concentrations of doxazosin were proportional to dose and the plasma half-life was 11.5 h and independent of dose. There was low variability of doxazosin plasma concentrations between patients receiving the same dose. Concentrations and half-life were unchanged during the period between investigations. Mean reductions of AUC (0-12 h) blood pressure during the 12-h period post-dose and of blood pressure at 24 h post-dose were not statistically different between doxazosin and atenolol. There was effective control of blood pressure by both drugs at all time points of the day. The pharmacokinetic and pharmacodynamic results obtained in this study are compatible with the use of doxazosin in a once daily dose regimen for the treatment of essential hypertension.

The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.

Pharmacokinetics and metabolism of 14C-tinidazole in humans.

Following intravenous infusion of 800 mg of 14C-tinidazole during 30 min to two human subjects, a mean of 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose during five days: 12% of the dose was excreted in the faeces, indicating the possible involvement of biliary excretion and other secretory processes in the disposition of tinidazole. At 6 min after the end of the infusion, the mean plasma tinidazole concentration was 12 mg/l. Tinidazole was a major component in 0-120 h urine (about 32% of urinary 14C): the major metabolite in the 0-12 h urine examined was ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone (about 30% urinary 14C), the product of hydroxylation and nitro-group migration. These compounds were also present in the faeces. A minor urinary metabolite was 2-hydroxymethyltinidazole (about 9% urinary 14C), which was also present in plasma. The mean pharmacokinetic parameters obtained for tinidazole were similar to those reported in the literature; total clearance 51 ml/min, renal clearance 10 ml/min, volume of distribution 501 and half-life 11.6 h.

The metabolism and kinetics of doxazosin in man, mouse, rat and dog.

The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C-labelled compound. Bioavailability and pharmacokinetic studies were also conducted with nonlabelled drug, using a specific h.p.l.c. method. Following both oral and intravenous administration, the major route of elimination of drug-related compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog. The drug is extensively metabolized, e.g. only about 5% of the dose was excreted unchanged in man. Metabolism in man mainly involves 6- and 7- O-demethylation and 6' and 7'-hydroxylation. These and some minor products were common to the mouse, rat or dog and man. Plasma protein binding was high in all species studied, ranging from 95.3% in the rat to 98.3% in human patients. Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63% reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min-1 kg-1 (dogs), 30 ml min-1 kg-1 (rats) and 1.2 ml min-1 kg-1 (human subjects). Mean plasma half-life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half-life of doxazosin provides the basis for once-daily dosing.

A novel metabolite of tinidazole involving nitro-group migration.

After oral doses to dogs of 14C-tinidazole, a 5-nitroimidazolyl antiprotozoal compound, a major and previously unidentified radioactive metabolite was isolated from urine and shown by FAB mass spectrometry and n.m.r. spectroscopy to be ring-hydroxylated. The exact identity of this metabolite was established by X-ray diffraction analysis as ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone. The apparent migration of the nitro group from the 5 position in the parent drug to the 4 position in the metabolite is a novel metabolic route.

Tioconazole, a new imidazole-antifungal agent for the treatment of dermatomycoses. Antifungal and pharmacologic properties.

Tioconazole is a new imidazole antifungal agent with broad-spectrum activity. Its in vitro activity against common dermal pathogens is generally better than miconazole by a factor of 2-8. This activity is paralleled by good topical efficacy in a guinea pig dermatomycosis model. Pharmacokinetic studies in animals have demonstrated minimal systemic exposure following dermal application. Acute general pharmacology studies have shown that the compound is well tolerated in animals and unlikely to produce side-effects in man.

The effect on plasma prolactin, growth hormone and luteinising hormone concentrations of single oral doses or propranolol and tolamolol in normal man.

In a placebo controlled double-blind study in six healthy male volunteers the effects of single oral doses of 100 mg and 200 mg of tolamolol on plasma concentrations of prolactin, growth hormone and luteinising hormone were investigated. In a second placebo controlled single-blind study in a further six healthy male volunteers the effects of single oral doses of 200 mg tolamolol and 160 mg propranolol on the same plasma hormone concentrations were compared. A dose dependent increase in plasma prolactin concentration was demonstrated after tolamolol. The increase in plasma prolactin concentration was not evident after propranolol. Plasma growth hormone and luteinising hormone concentrations were not significantly changed by either propranolol or tolamolol.

[Clearance concept applied to pharmacokinetics: 1. Application for the study of tolamolol (beta-blocking agent) in healthy volunteers (author's transl)]. / Le concept de clairance en pharmacocinétique: I. Application au comportement due tolamolol (beta-bloquant) dans les conditions normales.

Pharmacokinetics is often performed using models derived from the properties of exponential equations in order to analyse the behaviour of drugs in normal and pathological situations. A new approach based on the clearance concept allows an interpretation of the experimental data with models incorporating some physiological parameters, such as hepatic blood flow. The present study shows how the clearance concept may be used for the treatment of the results obtained in healthy volunteers. In particular, it allows an estimation of the importance of hepatic first-pass metabolism and validates the model used for the analyses of the kinetics of tolamolol.

Metabolism of [14C]phenol by sheep, pig and rat.

1. Following an oral dose of [14C]phenol (12.5 or 25 mg/kg) to sheep, pig and rat, urinary elimination of radioactivity was rapid, 80-90% dose being excreted in the first 8 h. 2. In anaesthetized, ureter-cannulated rats, 70-80% of an intraduodenal dose was eliminated in 2 h; 2% dose was excreted as phenol conjugates in the urine within 10 min. 3. The major urinary metabolites from phenol (25 mg/kg) were phenylglucuronide and phenylsulphate. In the sheep, pig and rat, the glucuronide accounted for 49%, 83% and 42% respectively, of the total urinary metabolites and sulphate accounted for 32%, 1% and 55%. Conjugates of quinol were minor urinary metabolites (less than 7%) in all three species. 4. In sheep some 12% of the urinary metabolites was conjugated with phosphate; this metabolite was not found in rat or pig.

Bioavailability of tolamolol.

Bioavailability of capsule and tablet formulations of tolamolol were compared by measuring plasma concentration of tolamolol and reduction in maximum exercise heart rate over a period of twelve hours in eight healthy subjects in a two-way cross-over study. Tolamolol was absorbed more rapidly from capsules than from tablets; this did not result in any significant difference in the reduction in maximum exercise heart rate between the two formulations. There was no significant difference between area under curve of reduction in exercise tachycardia and area under-curve of plasma concentration of tolamolol for the two formulations. Reduction in maximum exercise heart rate was related to logarithm of plasma concentration of tolamolol between two and twelve hours after both formulations.

Pharmacokinetic and pharmacological studies with tolamolol in man.

Pharmacokinetic and physiological variables were measured in six healthy subjects after intravenous and oral administration of tolamolol. 2. After intravenous injection of tolamolol (20 mg), there was a biphasic decline both in plasma concentration and attenuation of maximum exercise tachycardia. First and second phase half-lives of plasma concentration were 7 min and 2.5 h respectively. WReduction of maximum exercise tachycardia declined from 32 beats/min at 2 h to 19 beats/min at 8 hours. Clearance of tolamolol from blood ranged from 0.8-1.41 min-1. 3. After the oral administration of tolamolol (100 mg), the average volume of distribution was 220.1 and plasma concentration half-life 1.8 hours. After ten eight-hourly doses of 100 mg there was no accumulation of tolamolol and the half-life of plasma clearance was unchanged. 4. Hydroxytolamolol was detected in plasma in two of six subjects after oral tolamolol. 5. There was a significant positive correlation between reduction in maximum exercise heart rate and logarithm of plasma concentration of tolamolol after both oral and intravenous administration.