Nakahara Y, Takahashi K, Kikura R
National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
Biol Pharm Bull. 1995 Sep;18(9):1223-7. doi: 10.1248/bpb.18.1223.
To determine the mechanism involved, the incorporation rate (ICR) of drugs into hair was compared to melanin affinity, lipophilicity and membrane permeability. The following 20 drugs were tested; amphetamine, methamphetamine, p-hydroxyamphetamine, p-hydroxymethamphetamine, cocaine, benzoylecgonine, ecgonine methyl ester, morphine, 6-acetylmorphine, phencyclidine, 1-(1-phenyl)-piperidinyl-cyclohexanol, methylenedioxyamphetamine, methylenedioxymethamphetamine, methoxyphenamine, O-desmethyl methoxyphenamine, benzphetamine, norbenzphetamine, deprenyl, lysergic acid diethylamide (LSD) and 11-nortetrahydrocannabinol-9-carboxylic acid (THCA). Their ICRs were represented as the ratios of the drug concentrations in rat hair to AUCs (the areas under the concentration vs. time curves) in rat plasma. Cocaine had the highest incorporation rate understood and there was a 3600 fold difference between the ICR of cocaine and that of THCA, the lowest drug. The melanin affinity of these drugs was determined by incubating a test solution with melanin at 36 degrees C in the dark for 2 h. After incubation and centrifugation, the drug concentration in the filtrate was determined by GC/MS or LC. The drug most affinitive to melanin was cocaine, followed by benzphetamine, phencyclidine, methylenedioxymethamphetamine and LSD. The correlation coefficient between ICR and melanin affinity of the 20 drugs was 0.947 (0.949 excluding THCA). Lipophilicity was calculated from the retention times of HPLC according to Kaliszan's method. Although the correlation coefficient between ICR and lipophilicity was very low (0.201), it rose to 0.770 by removing only THCA. The combination of melanin affinity and lipophilicity brought about a higher correlation (0.979) with the ICRs. Our data also suggested that the higher ICRs of basic drugs than neutral or acidic ones are strongly related to the membrane permeability of the drug based on the pH gradient between blood (pH 7.4) and hair matrix (acidic).
为确定其中涉及的机制，将药物掺入毛发的速率（ICR）与黑色素亲和力、亲脂性和膜通透性进行了比较。测试了以下20种药物：苯丙胺、甲基苯丙胺、对羟基苯丙胺、对羟基甲基苯丙胺、可卡因、苯甲酰芽子碱、芽子碱甲酯、吗啡、6-乙酰吗啡、苯环利定、1-(1-苯基)-哌啶基环己醇、亚甲二氧基苯丙胺、亚甲二氧基甲基苯丙胺、甲氧苯丙胺、O-去甲基甲氧苯丙胺、苄非他明、去甲苄非他明、司来吉兰、麦角酸二乙酰胺（LSD）和11-去甲-四氢大麻酚-9-羧酸（THCA）。它们的ICR表示为大鼠毛发中药物浓度与大鼠血浆中AUC（浓度-时间曲线下面积）的比值。可卡因的掺入率最高，已知其ICR与最低药物THCA的ICR相差3600倍。通过将测试溶液与黑色素在36℃黑暗中孵育2小时来测定这些药物的黑色素亲和力。孵育和离心后，通过气相色谱/质谱（GC/MS）或液相色谱（LC）测定滤液中的药物浓度。对黑色素亲和力最高的药物是可卡因，其次是苄非他明、苯环利定、亚甲二氧基甲基苯丙胺和LSD。20种药物的ICR与黑色素亲和力之间的相关系数为0.947（排除THCA后为0.949）。根据Kaliszan的方法，从高效液相色谱（HPLC）的保留时间计算亲脂性。尽管ICR与亲脂性之间的相关系数非常低（0.201），但仅去除THCA后，该系数升至0.770。黑色素亲和力和亲脂性的组合与ICR的相关性更高（0.979）。我们的数据还表明，基于血液（pH 7.4）和毛发基质（酸性）之间的pH梯度，碱性药物比中性或酸性药物更高的ICR与药物的膜通透性密切相关。
