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 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 (C24 h): 22.8 +/- 8.3 versus 49.5 +/- 35.7 ng/ml, p < 0.05; AUC 1134.4 +/- 512.7 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/C24 h 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 micrograms/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 micrograms/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 micrograms/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. 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.

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 (Mosher's 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.

Gas chromatographic assay of glycerol mononitrates in biological samples.

A new gas chromatographic analysis of glycerol 1-nitrate and glycerol 2-nitrate is described. The method is suitable for a variety of biological samples and can detect down to the low nanogram range. An extract of the sample to be analysed is treated with phenylboronic acid. The glycerol mononitrates rapidly form cyclic boronates, with five- and six-membered rings, respectively, which can then be separated by gas chromatography and detected by an electron-capture detector.

Improved method for the rapid determination of isosorbide dinitrate in human plasma and its application in pharmacokinetic studies.

A rapid, accurate and highly sensitive method was developed for the determination of isosorbide dinitrate in human plasma. Concentrations in the lower nanogram and subnanogram range are determined by a one-step extraction of 2 ml plasma, containing 4 ng/ml nitroglycerine as internal standard, with 5.5 ml n-pentane. The extract is subjected to gas--liquid chromatography--electron capture detection analysis. The lower limit of quantitation is 200 pg/ml, but concentrations as low as 50 pg/ml are still detectable. The method allows the quantitative determination of isosorbide dinitrate plasma levels in man following a 5 mg sublingual administration up to four hours after application.