Percutaneous absorption of chlorhexidine in rats

Percutaneous absorption of the antimicrobial agent chlorhexidine (labelled with carbon-14) was studied in rats. Less than 5% of the topically applied chlorhexidine was absorbed during a 5-day period. Excretion of absorbed radioactivity occurred mainly in the faeces.     

Percutaneous absorption of formaldehyde in rats

As formaldehyde is used as a preservative in cosmetic products, its dermal absorption from an O/W-cream was studied using rats. [14C]Formaldehyde as a tracer, together with non-labelled formaldehyde, was incorporated into a cream at a total concentration of 0.1%. Approx. 5% of the applied radioactivity was absorbed percutaneously within 48 h. Higher values were not found under occlusive conditions. The labelled substance was excreted primarily in urine and exhaled air. Further radioactivity was found in the carcass. Based on these results, a rough approximation was attempted of the amount of formaldehyde which could penetrate human skin after the application of a formaldehyde-containing cosmetic.     

Percutaneous absorption of mercury vapor by rats

With respect to occupational exposure situations, more information is needed to assess the importance of the skin absorption route for elemental mercury. The purpose of the experiments reported here is to prove the suitability of the rat tail as a model of Hg skin uptake. A vapor generation system used with a tail-only exposure system is described and first results are reported. An Hg uptake via the rat tail skin could be confirmed. The Hg uptake rate cannot be estimated quantitatively by these experiments.     

Pharmacokinetics of nitroglycerin in rats.

The plasma nitroglycerin levels obtained after intracardial (0.7 mg/kg), oral (7 mg/kg), and topical (7--14 mg/kg) doses of nitroglycerin in rats are reported. Nitroglycerin followed essentially one-compartment kinetics after intracardial administration, showing a mean half-life of about 4 min and a mean apparent volume of distribution of about 3 liters/kg. After oral drug administration, "flip-flop" kinetics were evident. The mean oral bioavailability was determined to be 1.6%, firmly supporting the contention that nitroglycerin is extensively metabolized during first passage through the liver. Under the experimental conditions studied, no detectable levels of nitroglycerin were observed after topical application.     

Percutaneous absorption of drugs. IV. Percutaneous absorption of drugs from oily vehicles.

The percutaneous absorption and retention of salicylic acid and carbinoxamine from four oily vehicles (liquid paraffin, oleic acid, hexadecyl alcohol, and isopropyl myristate) were studied by employing a recirculation apparatus. The absorption followed first-order kinetics, with the exception of the initial period. The vehicle that had a strong affinity to the drug showed a poor drug-releasing effect, and poor absorption and retention of drugs by the skin were observed. Higher absorption rate constants were observed for damaged skin than intact skin. The acceleration of absorption because of skin damage, however, was not so great from liquid paraffin as from the aqueous solution. The amount of drugs retained in the damaged skin declined following the initial increase.     

Percutaneous absorption of 14C-labelled 2-chlorobenzaldehyde in rats. Metabolism and toxicokinetics

2-Chlorobenzaldehyde might be produced when a moist skin is exposed to the riot control agent CS. CS-hydrolysis to 2-chlorobenzaldehyde and malononitrile occurs both in vitro and in vivo. No quantitative data have thus far been reported with respect to the percutaneous absorption and the cutaneous biotransformation of 2-chlorobenzaldehyde. Percutaneous absorption, biotransformation and elimination of 14-C-labelled 2-chlorobenzaldehyde was investigated in the rat. Following IV (25 microliters/kg) and IP (37.5 microliters/kg) 14C-2-chlorobenzaldehyde administration to rats, the plasma radioactivity declined rapidly over a 24 h period with similar plasma radioactivity-time profiles. Following cutaneous administration (75 microliters/kg) in a closed glass-cup on the skin a slow skin penetration occurred as indicated by plasma radioactivity levels. A slow increase in plasma radioactivity was followed by a slow decline of radioactivity in plasma over a 3-day period. Most of the radioactivity was found in the urine with low levels in faeces and exhaled air. The cutaneously administered radioactivity was also partly recovered from the glass-cup. For the qualitative and quantitative determination of metabolites in urine, a thin layer chromatography-radioautography method was used. The metabolic patterns of urinary excreted metabolites following cutaneous application and systemic administration of 14C-2-chlorobenzaldehyde to rats were very similar. No parent compound was recovered from the rat urine. 2-Chlorohippuric acid was the principal urinary metabolite. Quantitatively, the urinary excretion of 14C-2-chlorobenzyl alcohol following cutaneous application differed substantially from that after the systemic administration. There was no evidence of storage in the skin or skin toxicity of 2-chlorobenzaldehyde following cutaneous application.     

Percutaneous absorption of drugs.

The skin is an evolutionary masterpiece of living tissue which is the final control unit for determining the local and systemic availability of any drug which must pass into and through it. In vivo in humans, many factors will affect the absorption of drugs. These include individual biological variation and may be influenced by race. The skin site of the body will also influence percutaneous absorption. Generally, those body parts exposed to the open environment (and to cosmetics, drugs and hazardous toxic substances) are most affected. Treating patients may involve single daily drug treatment or multiple daily administration. Finally, the body will be washed (normal daily process or when there is concern about skin decontamination) and this will influence percutaneous absorption. The vehicle of a drug will affect release of drug to skin. On skin, the interrelationships of this form of administration involve drug concentration, surface area exposed, frequency and time of exposure. These interrelationships determine percutaneous absorption. Accounting for all the drug administered is desirable in controlled studies. The bioavailability of the drug then is assessed in relationship to its efficacy and toxicity in drug development. There are methods, both quantitative and qualitative, in vitro and in vivo, for studying percutaneous absorption of drugs. Animal models are substituted for humans to determine percutaneous absorption. Each of these methods thus becomes a factor in determining percutaneous absorption because they predict absorption in humans. The relevance of these predictions to humans in vivo is of intense research interest. The most relevant determination of percutaneous absorption of a drug in humans is when the drug in its approved formulation is applied in vivo to humans in the intended clinical situation. Deviation from this scenario involves the introduction of variables which may alter percutaneous absorption.     

Percutaneous absorption: in vivo experiments.

The percutaneous absorption of esters of nicotinic acid has been studied in vivo in man. The time for erythema to be produced has been measured both when the ester is applied continuously and in 'pulse' experiments when the ester is removed before the erythema develops. The results show that the erythema is produced long before steady state diffusion across the epidermis is established and the penetration of methyl nicotinate is characterized by D/l2 = 2.3 X 10(-4)s-1 where D is the diffusion coefficient and l the thickness of the barrier. Results using glycerol water mixtures in the external phase show that the route of penetration for methyl nicotinate is through the interstitial channels and not through the keratinized cells. Data for absorption from various creams and ointments (Barrett et al 1964) show that the route is independent of the nature of the external phase. Steady state data for the absorption of salicylic acid and carbinoxamine through the abdominal skin of guinea-pigs (Arita et al 1970) show that the route of penetration does not change as the experiment proceeds. Data for the absorption of other substances (Michaels et al 1975) also fit the interstitial route.     

Percutaneous absorption: theoretical description.

Equations are derived to describe the percutaneous absorption of a substance through the epidermal barrier. The treatment includes interfacial barriers and allows for the depletion of the substance in the external phase. The equations are derived both for the continuous application and for pulse experiments where the drug is applied for a time, then removed, and the response occurs some time after the removal of the drug. Competition between the drug diffusing through the keratinized cells (transcellular route) and diffusing in the interstitial channels around the cells (intercellular route) is also considered.     

Percutaneous absorption of hexachlorophene in rats, guinea pigs and pigs

A comparative study of the percutaneous absorption of hexachlorophene (HCP) was undertaken in rats, guinea pigs and pigs. [14C]Hexachlorophene ([14C]HCP) was applied evenly over the shaved back of the animals at a dose of 40 microgram/cm2 skin surface. Urine and feces were collected at 24-h intervals for 5 days from animals kept in metabolism cages. Different methods were used for quantitating the percutaneous absorption of HCP. This study showed that skin permeability to HCP decreased in the following order: rat, guinea pig and pig. The permeability characteristics of the pig skin to topically applied HCP were comparable to the published human data. We suggest that pig may be a suitable animal model for studying the percutaneous absorption of antimicrobial drugs.     

Percutaneous absorption of hexachlorophene in the rat.

[¹⁴C]-hexachlorophene was applied to intact, clipped skins of adult rats in four different solvents and an aqueous detergent solution. As much as 55% of the applied radioactivity was absorbed through the skin in a 24-hr period. Dimethyl sulfoxide enhanced absorption of the germicide to the greatest extent and aqueous sodium lauryl sulfate (1%, $\text{w}\text{v}$) was the least effective. With both adult and weanling rats, the first measurable amount of radioactivity appeared in the venous blood in less than 1.5 hr, and maximum values were attained 12 hr after topical application of [¹⁴C]hexachlorophene. Approximately 27% of the applied radioactivity remained bound to the skin after 4 and 24 hr and was not removed by washing with acetone. Distribution of radioactivity in rats 8 and 24 hr after topical application of [¹⁴C]hexachlorophene was similar in weanling and adult rats. Most of the absorbed radioactivity appeared in the plasma, liver, small intestine, caecum, stomach, kidney, urine, and feces.     

Percutaneous absorption of the insecticides fenitrothion and aminocarb in rats and monkeys

The dermal penetration of 14C-ring-labeled fenitrothion and aminocarb was determined in rats and rhesus monkeys. In monkeys, 49 +/- 4% (t1/2 = 14 h) of the fenitrothion and 74 +/- 4% (t1/2 = 25 h) of aminocarb were absorbed from the forehead, while 21 +/- 10% (t1/2 = 17 h) fenitrothion and 37 +/- 14% (t1/2 = 31 h) aminocarb were absorbed from ventral forearm. Monkey forehead was 2.3 times and 2.0 times more permeable than the forearm for fenitrothion and aminocarb, respectively. In rats, 84 +/- 12% (t1/2 = 20 h) of the fenitrothion and 88 +/- 6% (t1/2 = 17 h) aminocarb was absorbed from the middorsal region. These results were corrected for incomplete excretion by intramuscular injections of fenitrothion in money, 95 +/- 7% (t1/2 = 12 h), and rat, 69 +/- 9% (t1/2 = 12 h), and aminocarb in monkey, 95 +/- 14% (t1/2 = 8 h), and rat, 63 +/- 6% (t1/2 = 15 h). These results suggest rapid dermal absorption of these pesticides in rats and monkeys and the use of these animal models for measuring dermal penetration is discussed.     

Percutaneous absorption: interfacial transfer kinetics.

A new rotating diffusion cell is described in which a solute diffuses through a rotating filter. The transport of the solute to both sides of the filter is controlled by the rotation. The filter is filled with an organic phase. The rate of transfer of the solute through the filter is determined by the transport and by the kinetics of the interfacial transfer reactions. Since the transport is controlled the rate constant for the transfer reaction can be measured. Results for eleven different systems are reported and it is found that the rate constants are all smaller than 10(-4) ms-1.