Pharmacodynamic measurement of percutaneous penetration enhancement in vivo

Enhanced skin penetration of hexyl nicotinate was measured in human subjects using laser Doppler velocimetry (LDV). The local pharmacodynamic response (vasodilatation) to hexyl nicotinate permitted the kinetics and extent of penetration to be evaluated following topical application of 10 mM drug in a 60:40 v/v propylene glycol: isopropyl alcohol vehicle. Prior to hexyl nicotinate administration, the application site was either untreated (control) or subjected to one of four 30-min pretreatments: (a) occlusion with a polypropylene chamber; (b) occlusion (as in a) in the presence of 0.3 mL of the vehicle; (c) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% 2-pyrrolidone; and (d) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% laurocapram (1-dodecylhexahydro-2H-azepin-2-one). The time-course and magnitude of the LDV response were characterized by the onset of action, time to peak, peak height, and area under the curve (AUC). The onset of action and time to peak were significantly shortened, and the peak height and AUC significantly increased with pretreatments a-d. For example, time to peak values were 35 +/- 4, 29 +/- 3, 22 +/- 5, 19 +/- 4, and 17 +/- 4 min for control and pretreatments a-d, respectively (n = 8). Pretreatments with vehicle, vehicle plus 2-pyrrolidone, and vehicle plus laurocapram did not cause LDV-detectable alterations in skin blood flow. The data support, therefore, a novel, simple, noninvasive, and objective demonstration of enhanced skin penetration of hexyl nicotinate in humans.