Distribution of griseofulvin in the rat: comparison of the oral and topical route of administration.

Effective penetration of griseofulvin across the dermal barrier has been achieved using an anhydrous solvent system of benzyl alcohol (10%), acetone (40%), and isopropanol (50%). There were quantitative differences in the relative accumulation of griseofulvin in skin compared with internal organs, when the topical and oral routes of administration were compared. The topical route enhanced localized concentrations of griseofulvin at the site of application, and these persisted for several days. After daily topical application a steady state was reached at day 3, when the diffusion across the skin barrier and epidermal loss seemed to equal the total amount applied to the skin surface. The application of griseofulvin topically, required a much smaller amount of drug to achieve similar integumentary levels compared with the amount required orally.

The in vitro liberation and the bioavailability of different brands of griseofulvin in plasma and urine in man.

The bioavailability of griseofulvin in three different brands, two microfine forms (Gricin = G, Likuden = L), and one ultramicrofine form (Gris-PEG = GP), was determined in plasma and urine in six healthy volunteers in a crossover study and compared with in vitro liberation data. GP shows a higher AUCo infinity (140 +/- 24 mumol . h . l-1) and Cmax (4.5 +/- 0.1 mumol . h-1) than the microsize brands of griseofulvin (AUCo infinity:58 +/- 7, and 45 +/- 6 mumol . h . l-1; Cmax:1.7 +/- 0.2, and 1.5 +/- 0.2 mumol . l-1; G and L, resp.), but the same tmax at the third hour. There results correspond with the in vitro liberation data. Contradictory results of the bioavailability are found by determining the amount of 6-Demethylgriseofulvin eliminated in urine. The elimination of this main metabolite after dosing with L is lower (0.18 +/- 0.02 mmol) than those of the other two brands, which do not differ (0.31 +/- 0.04; 0.32 +/- 0.02 mmol, G and GP, resp.). It is concluded that the determination of bioavailability only by means of the eliminated amount of a metabolite in urine may produce false results.

Fat contents of meals and bioavailability of griseofulvin in man.

The bioavailability of griseofulvin was followed in twelve healthy volunteers by measuring the urinary excretion of the major metabolite 6-demethylgriseolfulvin, after each volunteer had ingested one 500 mg griseofulvin tablet under (1) fasting conditions, (2) immediately after a typical low-fat and (3) high-fat Nigerian meals. An increase of about 70 and 120% absorption occurred with the ingestion of the low-fat and high-fat meals respectively compared to the fasting state (P less than 0.01). The maximum excretion rates of the free metabolite (Vmax.) were also significantly increased (P less than 0.01) following consumption of low and high fat meals. Our results thus suggest that the higher the fat content of the meals the higher the enhancement of the bioavailability of griseofulvin in man.

Influence of high fat diet on GI absorption of griseofulvin tablets in man.

A controlled crossover study was carried out on five volunteers to substantiate reported effects of fat intake on the bioavailability of griseofulvin. The urinary excretion of 6-demethylgriseofulvin was monitored for 24 h following the administration of 125-mg griseofulvin tablets in the fasting state and after a fatty diet. Statistical analysis of excretion data indicated a significant increase in both rate and extent of absorption of griseofulvin as a result of fat intake. Excretion rate profiles obtained permitted insight into mechanisms possibly involved in the observed drug-diet interaction.

TLC determination of griseofulvin in plasma and 6-demethylgriseofulvin in urine.

Fluorometric TLC procedures are described for the determination of griseofulvin in human plasma and 6-demethylgriseofulvin in human urine. Griseofulvin is extracted from plasma with ether, and its metabolite, 6-demthylgriseofulvin, is extracted from urine with benzene. Both compounds are subjected to TLC on silica gel plates. The plates are scanned using the fluorescent mode of a spectrodensitometer. For griseofulvin, the quantitation limit is 20 ng/ml of plasma and the recovery is 100%; for 6-demethylgriseofulvin, the limit is 1 microgram/ml of urine and the recovery is 90%. The methods were used to determine the plasma levels of griseofulvin and the amount of 6-demethylgriseofulvin excreted in the urine of human volunteers after a single oral dose of griseofulvin.

Chromatographic analysis of griseofulvin and metabolites in biological fluids.

A simple and accurate assay for the determination of griseofulvin and its metabolites in biological fluids using high-performance liquid chromatography is described. Using a reversed phase column and a mobile phase solvent of 45% acetonitrile in 0.1 M acetic acid, baseline separation of griseofulvin and several analogues was obtained. The described method allows one to quantitatively determine griseofulvin, 6-demethylgriseofulvin, and griseofulvic acid, a newly identified metabolite in man, in urine and plasma samples. Treatment of plasma samples prior to the analysis is simply made by deproteinizing the samples with an equal volume of acetonitrile. For urine samples, the procedure involves diethyl ether extraction with subsequent evaporation to dryness and reconstitution with the mobile phase solvent.

High-pressure liquid chromatographic assay for griseofulvin in plasma.

A high-pressure liquid chromatographic procedure was developed for griseofulvin assay in human plasma. The method utilized warfarin as an internal standard and easily quantitated griseofulvin plasma levels as low as 0.10 micrograms/ml. The method was compared to two fluorometric assay methods and was more specific for griseofulvin. Assay of 6-demethylgriseofulvin isolated from human urine demonstrated that this material was not responsible for the interferences apparent in the fluorometric procedures.

Gastrointestinal absorption of griseofulvin from corn oil-in-water emulsions: effect of amount of corn oil ingested in man.

The effect of the amount of emulsified corn oil ingested on the gastrointestinal absorption of griseofulvin in man was assessed after oral administration of 5, 10, 15, or 30 gm doses of a corn oil (40% w/w)-in-water emulsion dosage form, each containing 250 mg of microsize griseofulvin. For comparison, griseofulvin absorption from two-125 mg commercial tablets of ultramicrosize drug dispersed in polyethylene glycol 6;000 was also determined. Griseofulvin was almost completely absorbed from the microsize drug emulsions and ultramicrosize drug tablets, whereas 50% of an oral dose is absorbed from commercial microsize griseofulvin tablets. Only 4 gm of emulsified corn oil (as a 10-gm dose of emulsion) is required to maximize the uniformity and extent of griseofulvin absorptions. The emulsion dosage form is uniquely suited for pediatric use.

Liquid-solid chromatographic determination of 6-demethylgriseofulvin in urine.

A specific and quantitative liquid-solid chromatographic method for the determination of 6-demethylgriseofulvin in human urine is reported. The method consists of extraction into an organic solvent, addition of internal standard, and analysis by liquid-solid chromatography using a UV detector. Griseofulvin, if present, can be determined simultaneously. The sensitivity of the method is 6 mug/ml of urine. Total 6-demethylgrisefulvin is determined after hydrolysis of the glucuronide conjugate with glucuronidase-sulfatase enzyme solution. The method is well suited for the analysis of a large number of samples.