R. A. Yeates

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.

Antagonism of glycerol trinitrate activity by an inhibitor of glutathione S-transferase

The in vitro spasmolytic activity of glycerol trinitrate was measured on the KCl-contraction of aorta strips from the rabbit. In the presence of sulphobromophthalein, a known inhibitor of glutathione S-transferase, the dose-activity curve for the nitrate was displaced to the right. Much smaller displacements were obtained with the control spasmolytic substances--papaverine and S-nitroso-N-acetylpenicillamine. It was confirmed that sulphobromophthalein inhibits glutathione S-transferase activity in aorta homogenates. Aorta extracts did not detectably catalyze the reaction between glutathione and sulphobromophthalein and the glutathione level was not decreased by treating the intact aorta with sulphobromophthalein. It is concluded that sulphobromophthalein acts as a specific antagonist of the spasmolytic activity of glycerol trinitrate, probably as a result of its inhibition of glutathione S-transferase. It thus seems probable that glutathione and glutathione S-transferase are involved in the pharmacological activation of the organic nitrates.

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.

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.

COMPARISON OF ISOBUTYL NITRATE AND ISOBUTYL NITRITE : TOLERANCE AND CROSS-TOLERANCE TO GLYCERYL TRINITRATE

This study includes the first systematic comparison of an organic nitrate with the corresponding organic nitrite-isobutyl nitrate and isobutyl nitrite. The spasmolytic activity of the nitrite on isolated rabbit aortic strips was stronger, more rapid in onset, but less stable than the activity of the nitrate. In vitro tolerance to glyceryl trinitrate and isobutyl nitrite greatly weakened the activity of isobutyl nitrate, respectively, but had much less effect on isobutyl nitrite. Possible reasons for these differences are discussed.

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.

Fluconazol: Vergleich von Pharmakokinetik, Therapie und Empfindlichkeit der Sproßpilze in vitro

Zusammenfassung. Fluconazol penetriert gut in die untersuchten Gewebe bzw. Körperflüssigkeiten und erzielt eine schnelle Äquilibrierung der Konzentrationen zwischen unterschiedlichen Kompartimenten. Die nach intravenöser oder oraler Applikation dosisproportionale Pharmakokinetik und die nur langsame Elimination (t1/2 30 h) des Triazols aus dem Körper erleichtern eine Voraussage für die therapeutisch wirksame Dosierung. Die im Blut gemessenen Fluconazol‐Konzentrationen konnen auch bei Patienten auf verschiedene Gewebe (Lunge, Gehirn, gynäkologische Proben) bzw. andere Körperflüssigkeiten (Sputum, Speichel, Vaginalsekret) oder Exsudate projiziert werden. Im Liquor cerebrospinalis und Kammerwasser des Auges betragen die Konzentrationen des Antimy‐kotikums etwa 80% der Blutspiegel. Die überwiegend renale Ausscheidung von unverandertem Fluconazol bewirkt hingegen im Urin 10–20fach höhere Konzentrationen als im Blut. Dieses pharmakokinetische Profil, das Fluconazol in der Behandlung mykotischer Harnwegsinfekte per se begünstigt, erfordert allerdings bei Patienten mit eingeschränkter Nierenfunktion die Anpassung der systemischen Therapie an eine niedere Dosierung. Die Empfindlichkeit der Sproßpilze korreliert in vitro und in vivo mit den in verschiedenen Kompartimenten des Körpers gemessenen Fluconazol‐Konzentrationen.

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

Summary. 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 flaconazole 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 μg ml‐1was reached 5 min after ingestion of the suspension, compared with a value of 3 μg ml‐1some 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.

Pharmacokinetics of oral glycerol-1-nitrate.

SummaryThe plasma kinetics and urinary excretion of glycerol-1-nitrate (G-1-N), a water soluble metabolite of glycerol trinitrate with anti-anginal potential, have been investigated in healthy human volunteers following oral doses of 10, 20 and 40 mg tablets and 20 mg as drops. In all volunteers G-1-N was rapidly absorbed. The mean concentration-time curves peaked 40 min after administration of tablets at 144 ng/ml (10 mg), 308 ng/ml (20 mg) and 573 ng/ml (40 mg). After the drops the peak of 324 ng/ml occurred at 1 h. The areas under the G-1-N concentration-time curve and the G-1-N peak heights were linear with dose. Tablets and drops can be regarded as bioequivalent with respect to area under the curve and elimination half-life. The bioavailability of the 20 mg tablet relative to the 20 mg drops was 98.6% in terms of area under the curve. The mean apparent half-life of G-1-N elimination from plasma was 2.69±0.67 h (n=46). The mean residence time of G-1-N in the body was 4.65 h compared to 0.28 h for glycerol trinitrate after buccal administration. Female volunteers were found to have significantly lower areas under the curve than male volunteers. The difference was probably due to differences in body weight. Renal excretion does not play an important role in the elimination of oral G-1-N from the body. An overall average of 5.42% of the G-1-N dose was excreted in the urine; free drug accounted for 4.02% and conjugated drug for 1.40%.