Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines.

The contributions of several proposed mechanisms by which fatty acids and amines might increase skin permeation rates were assessed. Permeation rates of model diffusants with diverse physicochemical properties (naloxone, testosterone, benzoic acid, indomethacin, fluorouracil, and methotrexate) through human skin were measured in vitro. The enhancers evaluated were capric acid, lauric acid, neodecanoic acid, and dodecylamine. Increased drug solubility in the vehicle, propylene glycol (PG), in some cases accounted for the increases in flux in the presence of adjuvants, since permeability coefficients were unchanged. Partition coefficients of some drugs into isopropyl myristate or toluene were increased by the adjuvants, but this did not occur for combinations of an acid with a base (adjuvant-drug or drug-adjuvant). Increases in flux not accounted for by increases in drug solubility or partitioning were assumed to involve disruption of the barrier function of skin (increased skin diffusivity). All fatty acids increased skin diffusivity of naloxone, testosterone, indomethacin, and fluorouracil but not of methotrexate or benzoic acid. Dodecylamine increased skin diffusivity only for fluorouracil. Capric acid and dodecylamine, but not lauric acid or neodecanoic acid, increased the skin permeation rate of PG, suggesting that enhanced solvent penetration could also be involved as a mechanism for increased skin permeation of the drug. However, the increase in PG flux due to dodecylamine was nullified when methotrexate was added to the vehicle, possibly because of a dodecylamine/methotrexate interaction. These studies demonstrate that drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption each can contribute to increased skin permeation rates in the presence of fatty acids and amines.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dietary calcium on lead absorption, distribution, and elimination kinetics in rats.

A pharmacokinetic analysis of lead absorption, distribution, and elimination was conducted in rats maintained on calcium-deficient, control, and calcium-supplemented diets. Dietary calcium affected lead disposition in a number of ways. Systemic lead clearance after a 10-mg/kg intracardiac lead dose was approximately 25% lower than control in rats administered dietary calcium supplements. Intestinal absorption of 10 mg/kg po lead doses was not affected by the calcium supplements. In rats maintained on a calcium-deficient diet, systemic lead clearance was estimated to be 40% less than control. The apparent volume of lead distribution was increased. The apparent systemic availability of 1-, 10-, and 100-mg/kg oral lead doses was three- to fourfold greater than control in calcium-deficient rats. The percentage absorption was dose-dependent in control and calcium-deficient rats. The observed changes in lead absorption and systemic clearance associated with the calcium-deficient diet represent synergistic effects that could elevate blood lead accumulation and thus potentially influence susceptibility to lead toxicity.