Effects of local blood flow on the percutaneous absorption of the organophosphorus compound malathion: a microdialysis study in man

Abstract

Malathion [O,O-dimethyl-S-(1,2-dicarbethoxyethyl)phosphorodithioate] is an organophosphorus insecticide widely used in veterinary medicine and in humans for the treatment of lice. In this study, the rate of the percutaneous absorption of malathion has been measured in human skin, in vivo, using microdialysis. Malathion was detected in tissue dialysate within 30 min of its topical application to the skin of the volar surface of the forearm of healthy volunteers. The concentration of malathion in dialysate increased with lengthening duration of exposure to reach a steady state concentration at 2 h. Prolonged exposure to malathion caused a marked and long-lasting erythema localized to the area of contact. There was no evidence of local tissue oedema or of a neurogenically mediated flare or itch response following topical application. Reducing skin blood flow by the addition of the vasoconstrictor noradrenaline to the dialysis probe perfusate caused an eight-fold increase in the recovery of malathion in the dialysate, which failed to reach a steady state within 5 h. Together, these data confirm that malathion can be absorbed percutaneously and that its distribution within the cutaneous tissue space is influenced by local skin blood flow. They suggest that the increase in skin blood flow caused by malathion may itself play a significant role in enhancing its systemic uptake.

Effects of Blood Flow on the in Vivo Recovery of a Small Diffusible Molecule by Microdialysis in Human Skin

“…However, there is increasing awareness that recovery of solute from the tissue space by dialysis is subject to many variables, including mass transport processes between the blood and tissues (Bungay et al, 1990;Singh and Roberts, 1993;Borg et al, 1999;Sun et al, 2001). Indeed, recent studies in our own laboratory in which we used microdialysis to assess the distribution and clearance of an organophosphorus compound in human skin in vivo showed that local vasodilatation, caused by the compound itself, had a significant impact on dialysis recovery from the tissue space and, by implication, on the local and systemic distribution of the compound (Boutsiouki et al, 2001). We attempted to investigate this further in the present study by focusing on the influence of local blood flow on dialysis probe extraction through the correlation of recovery of sodium fluorescein with altered blood flow in human skin in vivo.…”

“…NA perfusion was maintained throughout the experiment. GTN, which has been shown to cause local vascular damage leading to hemostasis if delivered by microdialysis (Boutsiouki et al, 2001), was delivered to a second site using a patch (Transderm-Nitro 5; Novartis Pharmaceuticals UK Ltd., Surrey, UK) applied for 30 min before the start of fluorescein-probe perfusion. Perfusion of one of the probes beneath the GTN patch (retrieval probe) with PBS was initiated on application of the patch 30 min before the start of perfusion of the second (delivery) probe with the fluoresceincontaining perfusate.…”

Microdialysis Sampling for Investigations of Bioavailability and Bioequivalence of Topically Administered Drugs: Current State and Future Perspectives

“…The skin concentration of a topically applied drug will increase if the blood flow is diminished, whereas an increased blood flow enhances the uptake and subsequent systemic distribution and elimination of the drug from the skin [39] . Experimental studies which induce vasoconstriction or vasodilatation have demonstrated that the BA of topically as well as systemically applied test substances is highly influenced by changes in the microcirculation of the skin [69,97,128,129] -an influence much stronger than the influence of variations in probe depth.…”

The Role of Menthol in Skin Penetration from Topical Formulations of Ibuprofen 5% in vivo

“…Menthol is included in Deep Relief as a second active moiety, because it possesses pharmacological properties which are not only directly relevant to pain relief, per se, but can also have a profound effect on the pharmacodynamics of co-permeating species in vivo. The importance of modulating effects on the local microvasculature on skin penetration has been described by several authors [22][23][24] . In addition to its well-known cooling effect, menthol can stimulate skin nociceptors and initiate an axon refl ex with subsequent release of vasodilator peptides [25] , and an increase in skin temperature and underlying muscle temperature has been shown after topical application of a mixture of eucalyptus oil and menthol [26] .…”