Transportation and Metabolism of Prodrugs in Thai Human Skin
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Abstract
This study was to investigate the effect of physicochemical properties of nicotinic acid (NA) and its alkyl ester derivatives on both permeation and metabolism characteristics through Thai human skin. The horizontal (side by side) diffusion cell was used for all experiments in this study. Three alkyl ester derivatives of NA, methyl nicotinate (MN), ethyl nicotinate (EN) and butyl nicotinate (BN), were selected and used as the model prodrugs. Thai human skins were obtained from Srinagarind university hospital. The experiment of skin metabolism was conducted using skin homogenate at 37 °c. The concentrations of NA and its alkyl ester derivatives were determined by HPLC. Permeation profiles were plotted between cumulative permeated amount against time. The maximum steady state flux (J) was found as follows; MN (J =10.3493 mmol/cm2hr), EN (J = 2.2962 mmol/cm2/hr), BN (J = 0.3604 mmol/cm2hr) and NA (J =0.0552 mmol/cm2/hr), respectively. While the permeability coefficients (k) were as follows; EN (k =2.614lXlO-6 cm/sec), BN (k^ =9.6539Xl0-7 cm/sec), MN (kp =5.7496Xl0-7cm/sec) and NA (kp = 5.3093X10-8 cm/sec), respectively. The more lipophilic ester prodrug showed higher permeability through human skin. However, the k value of BN was lower than EN. Compared with EN, BN remained in the skin due to its higher partition coefficient. In this study, it was shown that the enzyme reaction of skin homogenates followed Michaelis-Menten S rule and BN showed high affinity to skin enzyme.
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