H. Laufen

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 radio-telemetric 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.

BIOAVAILABILITY OF FLUCONAZOLE IN THE SKIN AFTER ORAL MEDICATION

Summary. Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 μg ml‐1, sweat 4.58 μg ml‐1, dermis‐epidermis (without stratum corneum) 2.77 μg g‐1 and stratum corneum 73 μg g‐1. Thus, 4 h after the last dose the antimycotic attains a 40‐fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 μg g‐1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 μg g‐1. Even 4–5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2–3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses.

Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility

Summary. 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 concentrations 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 yitreous 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.

Equivalence of a high-performance liquid chromatographic assay and a bioassay of azithromycin in human serum samples.

Two sensitive methods for the determination of the azalide antibiotic azithromycin in human serum were compared. High-performance liquid chromatography (HPLC) and a microbiological assay were simultaneously applied to 768 serum samples obtained in a clinical study. There was excellent agreement between the azithromycin concentrations measured by HPLC and by the bioassay. The correlation coefficient for the two methods was r2 = 0.96. The precision and the sensitivity of the methods were found to be very similar.

Enantioselective gas chromatographic assay with electron-capture detection for amlodipine in biological samples

A sensitive enantioselective gas chromatographic assay has been developed for amlodipine, 2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine, a calcium channel blocking therapeutic agent. The assay involves conversion of the (+)-(R)- and (-)-(S)-enantiomers of amlodipine into their acyl derivatives with the chiral reagent (+)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Moshers reagent). Peak separation after chromatography of the diastereomers was larger than 85%, and the lower limit of detection in blood plasma was 0.02 ng/ml for each enantiomer. The method has been used for the measurement of amlodipine enantiomers in human, rat and dog plasma, and in various organs of the rat.

Comparative Tolerability of Intravenous Azithromycin, Clarithromycin and Erythromycin in Healthy Volunteers

ObjectiveTo compare the tolerability of intravenous azithromycin, clarithromycin, erythromycin and placebo.DesignA double-blind, double-dummy, placebo-controlled, four-way crossover study was conducted in 12 healthy male volunteers. The participants were randomised to receive 1-hour intravenous infusions of azithromycin 500mg (2 mg/ml) once daily, erythromycin 500mg (1 mg/ml) three times daily, clarithromycin 500mg (2 mg/ml) twice daily, or placebo (normal saline, 500ml) three times daily, with each regimen administered for 3 days. There was a minimum 4-week washout period before participants switched to an alternative regimen, in random sequence, until all four regimens had been completed. Participants were monitored for infusion site reactions and gastrointestinal (GI) adverse events.ResultsClarithromycin caused clinically significant infusion site pain in 92% of the 12 participants evaluated and was exclusively associated with phlebitis and inflammation. Areas under score-time curves (AUSs) rating the intensity of inflammation and pain were significantly higher for clarithromycin compared with azithromycin (p < 0.0005). Erythromycin infusion caused clinically significant abdominal pain or nausea in 25% of participants. The AUSs for GI tolerability were significantly different for erythromycin compared with azithromycin (p < 0.001). Discontinuation rates due to infusion site reactions were 0% for azithromycin, 50% for clarithromycin, and 8% each for erythromycin and placebo. Treatment with erythromycin was interrupted or discontinued as a result of abdominal pain in 17% of patients and as a result of nausea in 8% of patients.ConclusionsIntravenous azithromycin had better infusion site tolerability than clarithromycin and better GI tolerability than erythromycin. The superior tolerability of azithromycin may avoid the discontinuation of intravenous antimicrobial therapy in seriously ill patients and assist in reducing the duration of hospitalisation and the cost of patient management.

Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells.

Multidrug resistance is expressed not only by bacteria, but also by tumor cells and by some normal cells of the body. It enables eukaryotic cells to exclude not only cytostatic drugs but also non-cytostatic antibiotics. This was demonstrated in genetically engineered multidrug resistant (MDR) cells infected with the facultative intracellular bacterium Listeria monocytogenes for all macrolide antibiotics tested (azithromycin, clarithromycin, erythromycin, josamycin, roxithromycin and spiramycin). In these cells and in conventionally selected MDR cells higher concentrations of the macrolides were necessary to inhibit the growth of L. monocytogenes than in the respective parental cells. This effect was due to a reduced intracellular accumulation, which was shown with a biological assay for all macrolides tested. For azithromycin, the results of this test were confirmed by measurement of the intracellular concentrations with high-performance liquid chromatography (HPLC). Besides the macrolides, MDR cells excluded also antibiotics of other chemical groups which was shown for ciprofloxacin, clindamycin, rifampicin and the streptogramin derivative RP 59500. In addition, in conventionally selected cells higher concentrations of chloramphenicol, doxycyclin, ofloxacin and trimethoprim than in the respective parental cells were necessary to inhibit the growth of L. monocytogenes. In contrast, when using genetically engineered cells, no significant differences were found for these antibiotics. These differences might be due to a higher expression of multidrug resistance in the conventionally selected cells because these cells were also more effective in excluding rhodamine 123 in a flow cytometric assay. In conclusion, expression of multidrug resistance by eukaryotic cells leads to a reduced concentration of macrolides and other antibiotics in these cells and to an impairment of activity against intracellular bacteria.

The Pharmacokinetics of Extended-Release Formulations of Calcium Antagonists and of Amlodipine in Subjects with Different Gastrointestinal Transit Times

The influence of gastrointestinal (GI) transit times on the pharmacokinetics (PK) of three calcium channel blockers (CCBs), recommended for once‐daily dosing, was investigated. In a three‐way crossover design, the single‐dose PK of a controlled‐delivery formulation of 240 mg diltiazem (DIL), an extended‐release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AML) were compared in two groups of healthy subjects, with either slow (> 35 h) or rapid (< 15 h) GI transit, as assessed by the metal detector method (EAS II). GI transit significantly affected the PK of DIL. Mean PK parameters in the rapid versus slow transit group were the following: trough levels (C24h): 22.8 ± 8.3 versus 49.5 ± 35.7 ng/ml, p < 0.05; AUC 1135.2 ± 510.9 versus 1704.7 ± 1185.6 hng/ml, p < 0.05 (one‐sided). Neither AUC nor trough levels of FEL and AML were significantly influenced by transit times, nor was Cmax after any of the three treatments. Variations in PK parameters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times were significantly lower for AML compared to DIL and FEL (7% vs. 30% and 17%, p < 0.001 and p < 0.002, respectively). Peak‐to‐trough ratios (Cmax/C24h mean) were 1.8 ± 0.9 for DIL, 7.6 ± 3.5 for FEL, and 1.7 ± 0.2 for AML. In conclusion, the predictability of pharmacokinetic behavior both in conditions of rapid or slow GI transit is optimized in drugs with intrinsically slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation‐based once‐a‐day characteristics are sensitive to GI transit if these processes are rapid enough to interfere with the formulation‐specific release profile.

Accumulation of Fluconazole in Scalp Hair

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1‐cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 μg/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 μg/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150‐mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 μg/g.

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.