Sakamoto T, Tanaka A, Nakahara Y
Showa College of Pharmaceutical Sciences, Machida, Tokyo, Japan.
Life Sci. 1998;62(6):561-70. doi: 10.1016/s0024-3205(97)01153-3.
The incorporation of phencyclidine(PCP) and its three major hydroxylated metabolites, 1-(1-phenylcyclohexyl)-4-hydroxypiperidine(PCHP), trans-4-phenyl-4-piperidinocyclohexanol(t-PPC) and trans-1-phenyl-1-(4'-hydroxypiperidino)-4-cyclohexanol(t-PCPdiol) into rat hair was studied. Three Dark Agouti male rats were intraperitoneally administered with PCP x HCl at a dose of 0.5 or 1.0 mg/kg once a day for 10 successive days. The plasma samples were collected from 5 min to 360 min after injection of each drug. The hair samples were collected 28 days after the first administration. The hair samples were extracted with methanol-5N hydrochloric acid(20:1) for 1 h under sonication. The plasma and hair extracts were extracted or purified with Bond Elut Certify and the extracts were silylated for the determination of PCP and its metabolites by GC/MS. The plasma AUCs were as follows; PCP(2.03 microg x min/ml) > t-PCPdiol(0.60 microg x min/ml) > PCHP(0.11 microg x min/ml) > t-PPC (0.065 microg x min/ml), while the hair concentrations were as follows; PCP(7.51 ng/mg) > PCHP (1.22 ng/mg) > t-PPC(0.10 ng/mg) > t-PCPdiol (0.05 ng/mg). In view of their AUCs, the hair concentration of t-PCPdiol was quite low, whereas that of PCP was so high. PCHP, t-PPC or t-PCPdiol was separately administered as the parent drug to the rats, and then the plasma and hair samples were analyzed in the same manner as PCP experiments. The incorporation rates ([hair concentration]/[AUC]) of PCP and its hydroxylated metabolites were as follows; PCP(2.29) > PCHP(0.79) > t-PPC(0.36) > t-PCPdiol(0.32). These data suggest that the decrease in lipophilicity caused by the hydroxylation of PCP suppresses the incorporation of the metabolites from blood into hair and the hydroxylation on cyclohexane ring(t-PPC) induces the decrease of the drug incorporation into hair more than that on piperidine ring(PCHP).
研究了苯环己哌啶（PCP）及其三种主要羟基化代谢物1-（1-苯基环己基）-4-羟基哌啶（PCHP）、反式-4-苯基-4-哌啶环己醇（t-PPC）和反式-1-苯基-1-（4'-羟基哌啶基）-4-环己醇（t-PCP二醇）在大鼠毛发中的掺入情况。选用三只深色刺豚鼠雄性大鼠，每天腹腔注射一次PCP盐酸盐，剂量为0.5或1.0mg/kg，连续注射10天。在每次注射药物后5分钟至360分钟采集血浆样本。首次给药28天后采集毛发样本。毛发样本用甲醇-5N盐酸（20:1）在超声处理下提取1小时。血浆和毛发提取物用Bond Elut Certify进行提取或纯化，提取物经硅烷化处理后用气相色谱/质谱法测定PCP及其代谢物。血浆曲线下面积（AUC）如下：PCP（2.03μg·min/ml）＞t-PCP二醇（0.60μg·min/ml）＞PCHP（0.11μg·min/ml）＞t-PPC（0.065μg·min/ml），而毛发浓度如下：PCP（7.51ng/mg）＞PCHP（1.22ng/mg）＞t-PPC（0.10ng/mg）＞t-PCP二醇（0.05ng/mg）。鉴于它们的AUC，t-PCP二醇的毛发浓度相当低，而PCP的毛发浓度则很高。将PCHP、t-PPC或t-PCP二醇分别作为母体药物给予大鼠，然后以与PCP实验相同的方式分析血浆和毛发样本。PCP及其羟基化代谢物的掺入率（[毛发浓度]/[AUC]）如下：PCP（2.29）＞PCHP（0.79）＞t-PPC（0.36）＞t-PCP二醇（0.32）。这些数据表明，PCP羟基化导致的亲脂性降低抑制了代谢物从血液掺入毛发，环己烷环上的羟基化（t-PPC）比哌啶环上的羟基化（PCHP）更能导致药物掺入毛发的减少。
