Accumulation of fluconazole in sebum.

Concentrations of fluconazole in sebum and plasma were determined in 2 parallel groups, each consisting of 8 healthy subjects. Group 1 received a 150 mg fluconazole capsule once weekly over a period of 4 weeks, Group 2 was administered 2 capsules/week, corresponding to 300 mg fluconazole/week for 4 weeks. Sampling was performed immediately before and 5 hours after dosing, and at intervals up to 2 weeks after the last dose. Fluconazole concentrations were determined by a specific and highly sensitive gas chromatographic method. Both treatments were well tolerated. Maximum fluconazole concentrations (mean +/- SD) in plasma were 3.5 +/- 1.0 microg/ml (Group 1) and 5.5 +/- 1.0 microg/ml (Group 2); maximum sebum concentrations were 11.0 +/- 8.4 microg/g (Group 1) and 48.4 +/- 37.0 microg/g (Group 2). Significant accumulation of fluconazole in sebum relative to plasma was observed. Sebum/plasma ratios ranged from 1.6 to 6.5 (Group 1) and from 4.3 to 27.9 (Group 2), with median ratios of 2.4 and 9.1, respectively. The overall accumulation factor was 7. The findings may be of particular relevance for the treatment of dermal mycoses involving the sebaceous glands, especially those associated with hair, such as tinea capitis.

The uptake of fluconazole in finger and toe nails.

OBJECTIVE: The uptake of the antimycotic agent fluconazole in finger and toe nail following various treatment schedules was investigated in order to characterize the pharmacokinetic basis for the systemic treatment of onychomycosis with fluconazole. SUBJECTS: Between 8 and 12 healthy, male and female Caucasian subjects were included in four separate studies. Mean age of the subjects in the single studies ranged between 34 years (study 4, group 2; n = 4 male and 4 female) and 38 years (study 4, group 1; n = 4 male and 4 female). METHODS: Fluconazole was administered orally over 4 weeks in all studies. The treatment schedules were 150 mg once weekly (study 1), 300 mg once weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once weekly in a parallel group study (study 4). At fixed times samples of blood, nail cuttings and nail dust were taken, up to two months after end of treatment. Fluconazole was analyzed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. RESULTS: High concentrations of fluconazole were found in distal nail clippings with all three treatments. Mean maximum concentrations which occurred in the third or fourth week of treatment amounted to 2.1 microg/g (150 mg/w), 5.4 microg/g (300 mg/w) and 6.5 microg/g (50 mg/d) in finger nails and to 9.6 microg/g (150 mg/w), 12.3 microg/g (300 mg/w) and 12.2 microg/g (50 mg/d) in toe nails. The nail concentrations were 1-2 times (finger) and 2-3 times (toe) higher than the corresponding fluconazole plasma levels and were within the MIC range for dermatophytes and yeasts occurring commonly in onychomycosis. The residence times of fluconazole in the nail plate after the end of treatment was long, with approximate half-lives of 33 days in finger nail and 30 days in toe nail. In pharmacokinetic terms there was no evidence of advantages of the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazole was found to penetrate into both finger and toe nails at a very fast rate. On the first two days of the 150 mg/w and 300 mg/w treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amounted to 50-80% of the later observed peak levels. The initial concentrations in the upper dorsal plate were particularly high, with mean peak concentrations of 11.9 microg/g (150 mg) and 33.7 microg/g (300 mg) in finger nails and 5.7 microg/g (150 mg) and 24.4 microg/g (300 mg) in toe nails. CONCLUSIONS: Fluconazole is rapidly and highly distributed into finger and foot nail, reaching there higher concentrations than in the plasma. The rapid initial uptake of fluconazole in nail, which is unlike the uptake of other antifungal agents, suggests the existence of special routes of access to the nail for fluconazole, possibly based on high diffusion rates.

Fluconazole concentrations in pulmonary tissue and pericardial fluid.

In order to investigate the clinical efficacy of the triazole antifungal agent fluconazole (FCA) in the treatment of pulmonary mycosis, in the present study the concentrations of fluconazole in human pulmonary tissue, pericardial fluid and serum were determined at 1, 2, 12 and 13 h after intravenous administration of fluconazole 200 mg. The mean FCA concentrations in the serum were 4.04 mg/l (1 h), 3.82 mg/l (2 h), 2.35 mg/l (12 h) and 2.13 mg/l (13 h). The respective FCA levels in the pulmonary tissue were 4.64 mg/kg, 4.54 mg/kg; 3.50 mg/kg and 3.40 mg/kg and the concentrations in the pericardial fluid were 3.86 mg/l, 3.57 mg/l, 2.35 mg/l and 2.13 mg/l. The FCA concentrations in the pulmonary tissue that were statistically significant higher than the serum concentrations were found at 2 h, 12 h and 13 h after intravenous administration (p < 0.05).

Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility.

Fluconazole shows good penetration into the tissues and body fluids examined and a rapid equilibrium is achieved between the concentrations in the various compartments. The pharmacokinetics of fluconazole after intravenous or oral administration are proportional to the dose. This finding, together with the slow elimination of the triazole (t1/2 30 h), makes it easier to forecast the therapeutically effective dosage. Measurements of fluconazole concentration in blood can be used to predict levels in some tissues (lung, brain, gynaecological samples), body fluids (sputum, saliva, vaginal secretions) or exudates. Concentrations in cerebrospinal fluid and vitreous humour of the eye reach approximately 80% of the levels found in blood. A very high proportion of fluconazole is excreted unchanged in the urine, where concentrations of the drug are 10-20-fold higher than in blood. Whilst this pharmacokinetic profile is valuable in the treatment of fungal infections of the urinary tract, it also means that the dosage may need to be decreased in patients with renal impairment. The susceptibility of fungi to fluconazole in vitro and in vivo correlates well with the concentrations of the drug measured in various compartments of the body.

Pharmacokinetic and pharmacodynamic interaction study between midazolam and the macrolide antibiotics, erythromycin, clarithromycin, and the azalide azithromycin.

This report includes a recalculation of the pooled data of 2 pharmacokinetic and pharmacodynamic studies of the interaction between the hypnotic midazolam and the antibiotics erythromycin, clarithromycin (macrolides), and azithromycin (an azalide). Erythromycin and clarithromycin similarly and strikingly impaired the metabolism of midazolam and enhanced its pharmacodynamic activity; little or no effect was found with azithromycin. It was concluded that coadministration of midazolam and azithromycin involves less clinical risk than with the 2 macrolides.

A new pharmaceutical concept for the treatment of oropharyngeal and oesophageal candidosis with fluconazole.

Administration of fluconazole in capsule form has proved effective in the prophylaxis and treatment of mucosal candidosis, particularly in immunosuppressed patients. An additional topical effect in oropharyngeal and oesophageal candidosis might be expected with a fluconazole suspension. This hypothesis was therefore tested in a crossover study in 12 healthy volunteers in whom the concentrations of the antimycotic were measured in saliva and plasma after oral administration of 100 mg fluconazole as either a capsule or a suspension. The time courses of the fluconazole concentrations were very similar with the two formulations in plasma, but significantly different in saliva. Thus, the mean Cmax for fluconazole in saliva of 551 micrograms ml-1 was reached 5 min after ingestion of the suspension, compared with a value of 3 micrograms ml-1 some 4 h after taking the capsule. The mean concentration of the antimycotic in saliva over the observation period (0-96 h) was more than 80% higher with the suspension than with the capsule.

Interaction between midazolam and clarithromycin: comparison with azithromycin.

A comparative pharmacokinetic and pharmacodynamic investigation was carried out on the interaction between the hypnotic midazolam and 2 different macrolide-type antibiotics, clarithromycin and azithromycin. In an open randomized crossover study of 3 phases 12 healthy volunteers received either clarithromycin (250 mg twice a day for 5 days), azithromycin (500 mg once a day for 3 days) or no pretreatment. On the last day of antibiotic treatment they ingested 15 mg midazolam. Plasma samples were collected for midazolam analysis up to 24 h and pharmacodynamic performance measured by a series of tests up to 12 h. Pretreatment with clarithromycin caused large and statistically significant changes in both the pharmacokinetic and pharmacodynamic parameters of midazolam compared to control. For example, the AUC was increased from 248.84-888.75 hng/ml (factor of 3.57, p < 0.0001) and the mean duration of sleep increased from 135.4 min to 281.3 min (p < 0.05). No statistically significant effect was found with azithromycin in any test. It is concluded that a drug interaction exists between midazolam and clarithromycin which could be of clinical importance. No such effect is present with azithromycin.

Screening for cytochrome P450 3A in man: studies with midazolam and nifedipine.

This report describes work directed towards the development of a screening technique for cytochrome P450 3A activity which should be valid for a variety of drugs metabolized by this enzyme. A significant correlation (P < 0.01) was found between the ratio of the plasma concentration of nifedipine to that of its oxidized metabolite and the area under the time curve for the plasma concentration of midazolam. It is suggested that the nifedipine: metabolite ratio might have general predictive value for the metabolism of orally administered cytochrome P450 3A substrates.

Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam.

The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h.ng.ml-1 vs. (E) 662.7 h.ng.ml-1*+ and (A) 220.0 h.ng.ml-1; concentration maxima (C) 67.2 ng.ml-1 vs. (E) 182.3 ng.ml-1*+ and (A) 86.7 ng.ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h* and (A) 2.41 h (* p < 0.05 vs. (C), +p < 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.

[Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility of yeasts]. / Fluconazol: Vergleich von Pharmakokinetik, Therapie und Empfindlichkeit der Sprosspilze in vitro.

Fluconazole penetrates well into the tissues and body fluids which were examined and achieves rapid equilibration between the different compartments. The pharmacokinetics of fluconazole are independent of the dose after oral or intravenous administration. This finding, together with the drug's slow elimination (t1/2 30 h) facilitate the estimation of the therapeutically effective dosage. The concentrations of fluconazole measured in blood can be extrapolated to the concentrations in tissue (lung, brain, gynecological tissues), body fluids (sputum, saliva, vaginal secretions) and exudates. The concentration of fluconazole in cerebrospinal fluid and in the vitreous humour of the eye is ca. 80% of that in blood. Fluconazole is predominantly excreted in the urine in the unchanged form, which explains the 10 to 20 fold higher concentration of the drug in urine relative to blood. Although this pharmacokinetic profile favours the use of fluconazole in mycotic infections of the urinary tract it also means that the dose of the drug may have to be adapted to lower regimens in the systemic treatment of patients with restricted kidney function. The in vitro and in vivo susceptibility of the yeasts correlates with the concentrations of fluconazole measured in the different compartments of the body.

[A new pharmaceutical concept for the therapy of oropharyngeal and esophageal candidiasis with fluconazole]. / Ein neues pharmazeutisches Konzept für die Therapie der oropharyngealen und oesophagealen Candidose mit Fluconazol.

Administration of fluconazole capsules is of proven worth in the treatment of candidosis of the mucous membranes, particularly in immunocompromised patients. An additional topical effect on the course of oropharyngeal and oesophageal candidosis can be expected when fluconazole is administered as a suspension. For this reason a crossover pharmacokinetic study with 12 healthy volunteers was carried out, in which the concentrations of the antimycotic were measured in saliva and plasma, after oral administration of 100 mg fluconazole as either a capsule or as a suspension. The time-courses of the concentration of fluconazole after the two formulations were very similar in plasma, but significantly different in saliva. The mean Cmax for fluconazole in saliva was 551 micrograms/ml 5 min after ingestion of the suspension and 3 micrograms/ml 4 h after taking the capsule. Over the observation time (0-96 h) the concentration of the antimycotic in saliva was more than 80% higher with the suspension than with the capsule.

Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis.

The pharmacokinetics of a single 100 mg i.v. dose of fluconazole were studied in parallel groups of ten normal subjects and nine patients with liver cirrhosis, a condition with a high risk of life-threatening fungal infection. The following mean pharmacokinetic parameters were found for the patient group: terminal elimination constant 0.0101/h (normal 0.0214/h); mean residence time 134 h (normal 46.7h); area under the curve 200 h.mg/L(normal 69.4 h.mg/L); plasma clearance 0.96 L/h.kg(normal 2.16 L/h.kg). All these differences were statistically significant (P < 0.05). The majority of the patients were being concomitantly treated with duretics (frusemide and spironolactone). It is suggested that the known slight interaction between such drugs and fluconazole was intensified by the disease state. These results emphasize the need for caution in the treatment with fluconazole of patients with severe liver disease. Nevertheless, in view of the wide range of values found in the patients, and low toxicity of fluconazole, a dosage reduction in cirrhosis does not seem to be justified in the present state of knowledge.

Comparative pharmacokinetics of fluconazole and of itraconazole in Japanese and in German subjects.

In separate but identically designed studies the oral pharmacokinetics of 100 mg doses of the 2 antimycotics fluconazole and itraconazole were examined in Japanese and German subjects (both n = 12), both fasting and concomitant to a heavy breakfast. The results with the 2 races were compared. With fasting subjects no significant difference was found with either antimycotic for any parameter. With fluconazole the pharmacokinetic parameters after food were essentially the same for the 2 races. The only significant difference, a delay of 1.5 h in the median tmax in the Japanese relative to the Germans, should not be of practical importance. In contrast, the mean AUC for itraconazole in Japanese subjects after the meal was only 54.9% of the value with Germans (p < 0.05); the corresponding Cmax was only 54.7% (p < 0.01). As itraconazole is normally administered together with food, this suggests that there is a possibility of underdosage in Japanese subjects. There appears to be no such problem with fluconazole.

Pharmacokinetic optimization of the treatment of oral candidiasis with fluconazole: studies with a suspension.

An open crossover study was performed in 12 healthy subjects to investigate the pharmacokinetics in saliva and plasma of a 100 mg oral dose of fluconazole, administered as either a capsule or as a suspension, the latter being used to rinse the mouth and retained for 2 min before being swallowed. In terms of fluconazole plasma concentrations the capsule and the suspension were essentially bioequivalent. While the saliva concentrations of fluconazole after capsule administration reached their peak at 3.0 +/- 0.8 micrograms/ml 4 h after dosage, administration of the suspension resulted in a mean peak concentration of 551.1 +/- 425.6 micrograms/ml 5 min after ingestion. The saliva concentrations decreased gradually after ingestion of the suspension, but were higher for 4 h than the corresponding levels from the capsule. The area under the curve (AUC) from 0 to 96 h of fluconazole in saliva was 227.7 +/- 73.8 h micrograms/ml after the suspension, compared to 123.5 +/- 25.5 h micrograms/ml after the capsule, indicating that the total drug exposure to the oral mucosa by the salivary route was enhanced more than 80% with use of the suspension. Four h after administration of the suspension, saliva and plasma concentrations of fluconazole were in equilibrium, at a saliva: plasma ratio of around 1.2. Taken together, the present results suggest that the treatment of oral candidiasis with fluconazole may be optimized by use of an oral suspension, as this delivers pharmacologically active levels of the drug to the site of infection by both topical and systemic routes.

Influence of doxazosin on the activity of the endothelium-derived relaxing factor.

This work examined the effect of the selective a1-inhibitor, doxazosin (CAS 74191-85-8), on the activity of endothelium-derived relaxing factor (EDRF). In vitro, the intact thoracic aortic rings of rabbits were contracted with the a-agonist, phenylephrine, and then relaxed by sequentially increasing concentrations of the EDRF-releasing agent adenosine triphosphate (ATP). In parallel experiments, doxazosin (10(-8) mol/l) was added after the contraction but before the addition of ATP. Doxazosin enhanced the ATP-induced vasodilation by a factor of 3. Control experiments suggested that this was due to the enhanced activity of EDRF, which was related to displacement of phenylephrine from a1-adrenoceptors by doxazosin. Physiologically relevant concentrations of 6- or 7-hydroxydoxazosin (5 x 10(-10) mol/l) had no effect on EDRF activity in vitro. In vivo experiments in the rabbit were carried out using bolus, intravenous injections of acetylcholine (ACh), which stimulated EDRF release. Threshold doses of doxazosin (2 x 10(-6) g/kg) enhanced the hypotensive activity of ACh. Prefeeding the rabbits for 4 weeks with a 2% cholesterol diet significantly reduced the sensitivity of the aorta to isosorbide-5-mononitrate, a stable EDRF-analog. However, the impairment in endothelium-dependent relaxation was attenuated in the presence of doxazosin (2 x 10(-9) mol/l). The results that in addition to its known antiplatelet activity, doxazosin enhances EDRF activity.

The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of omeprazole.

AIDS patients may have achlorhydria, a condition that could result in drug malabsorption, especially of antifungals. The effect of a reduction in the production of gastric acid on the pharmacokinetics of the antimycotic fluconazole after a single 100 mg dose was investigated in a randomized two-way crossover study with 12 healthy volunteers. Gastric acid production was reduced by pretreatment with 20 mg omeprazole/day over a period of 7 days; pH and gastric emptying times were measured by a radiotelemetering pH capsule. Omeprazole pretreatment significantly raised the median gastric pH (from pH 1.1 to pH 4.7, p < 0.0001), but had no significant influence on gastric emptying time of the pH capsule (median = 4.3 vs 4.9 hours). The pharmacokinetics of fluconazole were unchanged; plasma parameters were Cmax = 2.04 micrograms/ml, tmax = 4.08 h and AUC = 98.91 h micrograms/ml after the omeprazole treatment, compared to 2.06 microliters/ml, 3.92 hours and 97.29 h micrograms/ml, respectively. The median bioavailability ratio of fluconazole before and after omeprazole treatment was 1.00. It is inferred that there is no interference of omeprazole with the plasma pharmacokinetics of fluconazole. The findings suggest that changes in gastric pH, as in patients with AIDS or those being treated with anti-ulcer drugs, should not influence the pharmacokinetics of fluconazole.

The pharmacokinetics of fluconazole after a single intravenous dose in AIDS patients.

The pharmacokinetics of fluconazole after a single 100 mg i.v. dose were studied in 10 healthy subjects (5 M; 5 F) and 10 HIV-positive patients (8 M; 2 F). The mean value of plasma clearance was 25% lower in the patient groups (17 +/- 6 (s.d.) vs 23 +/- 4 ml min-1; 95% CI of difference -11 to -0.7; P < 0.05). This difference may have been related to slightly reduced kidney function in the patient group (mean creatinine clearance -18%) but is unlikely to be clinically significant. Therefore, no adjustment of the dose of intravenously administered fluconazole appears to be necessary in AIDS patients without clinical signs of enteropathy.

Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in Japanese subjects.

The effect of food intake on the pharmacokinetics of orally administered fluconazole or itraconazole was investigated in a single-dose randomized two-way crossover study in Japanese subjects. 100-mg capsules of fluconazole or itraconazole were given to two parallel groups, each of 12 male and female volunteer subjects, and plasma concentrations of the antimycotics were determined by specific assays. Gastric pH and gastric emptying times were measured by coadministration of a radiotelemetric pH capsule. Intersubject variations in drug plasma concentrations were found to be much higher with itraconazole than with fluconazole. The coefficient of variation of the AUC (0-72) after food amounted to +/- 62% for itraconazole and +/- 16% for fluconazole. The consumption of a heavy breakfast significantly delayed the tmax of both drugs by approximately two hours (p < 0.05). This effect was accompanied by a significant prolongation of gastric emptying times (p < 0.0001). Food intake had essentially no effect on the absorbed amounts of fluconazole. The median relative bioavailability (postprandial vs fasting) based on AUC (0-72) was f = 0.99, with an individual range from 0.72 to 1.15. The corresponding Cmax ratio was 1.04 (range 0.91-1.17). The effect of food on the bioavailability of itraconazole was highly variable: it ranged from marked reductions (f = 0.35) to large increases (f = 3.74) of the AUC (0-72), at a median ratio of f = 1.23. The Cmax ratios postprandial vs fasting ranged between 0.27 and 5.71 (median = 1.04). It is concluded that food had an unpredictable effect on the extent of itraconazole absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of the antimycotic agents fluconazole and itraconazole to leukaemia patients: a comparative pharmacokinetic study.

This report presents the results of a randomized parallel design comparative study of the serum concentrations of fluconazole and itraconazole after administration of 100 mg orally to patients with leukaemia. Each group consisted of ten patients. The antimycotic drugs were administered with a standard breakfast immediately before the start of chemotherapy (day one) and on days eight and fifteen. No significant differences (p > 0.05; ANOVA) in the pharmacokinetic parameters of fluconazole (AUC, Cmax, Tmax) were found during the three days of the trial. It is concluded that there is no clinically important pharmacokinetic interaction between fluconazole and the chemotherapeutic agents given to this group of patients. A pharmacokinetic interaction between fluconazole and the fever suffered by some of the patients also seems unlikely. No significant differences (p < 0.05; ANOVA) in the pharmacokinetic parameters of itraconazole (AUC, Cmax, Tmax) were found during the three days of the trial, although the statistical power of the data was low. The significantly greater variability of all pharmacokinetic parameters for itraconazole than for fluconazole and the sharp increases and decreases in AUC during the course of the trial found for some patients in the itraconazole group suggest the need for caution in this group of patients.

Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole.

The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radiotelemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food. The plasma AUC and Cmax of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41-77%) on an empty stomach and 86% (65-102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100-115%) and 102% after the light meal (88-103%), and the criteria for bioequivalence were attained. Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.