Chang W H, Lin S K, Jann M W
Laboratory of Biological Psychiatry, Taipei City Psychiatric Center, Taiwan, Republic of China.
J Clin Psychopharmacol. 1991 Apr;11(2):99-105.
Plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were measured in 8 schizophrenic patients, neuroleptic-free for at least 4 weeks, after repeated oral administrations of 10 mg HAL and RHAL. Each agent was given for 10 days with a 2-week washout period between the two compounds. HAL and RHAL were interconverted in all subjects. Plasma RHAL/HAL ratios at steady state during HAL treatment were significantly greater than the HAL/RHAL ratios after repeated reduced HAL administration (0.51 +/- 0.12 vs. 0.16 +/- 0.04 SD, p less than 0.0005). This result suggests that the interconversions between HAL and RHAL are apparently not equivalent in humans. A negative correlation was found between RHAL/HAL ratios after HAL administrations and HAL/RHAL ratios after RHAL administrations (r = -0.82, p less than 0.05). Repeated injections of HAL or RHAL at low (0.1 mg/kg) or high (1.0 mg/kg) doses were conducted in guinea pigs. Drug concentrations in striatum and plasma were measured. Both RHAL/HAL ratios after HAL injections and HAL/RHAL ratios after RHAL injections were dose- and time-dependent. High doses and repeated injections produced greater RHAL/HAL ratios after HAL and smaller HAL/RHAL ratios after RHAL than those observed with low doses and single injections, respectively. Compared with the results obtained from schizophrenic patients, the conversion from HAL to RHAL in guinea pigs was greater than that in humans, but the back conversions appeared to be similar between the guinea pigs and humans. Based upon the dose-dependent increase in RHAL/HAL ratios, a hypothesis of the therapeutic window effect for HAL treatment is proposed.
在8名至少4周未服用抗精神病药物的精神分裂症患者中，在重复口服10毫克氟哌啶醇（HAL）和还原氟哌啶醇（RHAL）后，测量了血浆中氟哌啶醇（HAL）和还原氟哌啶醇（RHAL）的浓度。每种药物给药10天，两种化合物之间有2周的洗脱期。在所有受试者中，HAL和RHAL可相互转化。HAL治疗期间稳态时的血浆RHAL/HAL比值显著高于重复给予还原HAL后（RHAL）的HAL/RHAL比值（0.51±0.12对0.16±0.04标准差，p<0.0005）。这一结果表明，HAL和RHAL之间的相互转化在人类中显然并不等同。在给予HAL后的RHAL/HAL比值与给予RHAL后的HAL/RHAL比值之间发现了负相关（r = -0.82，p<0.05）。在豚鼠中以低剂量（0.1毫克/千克）或高剂量（1.0毫克/千克）重复注射HAL或RHAL。测量纹状体和血浆中的药物浓度。HAL注射后的RHAL/HAL比值和RHAL注射后的HAL/RHAL比值均呈剂量和时间依赖性。高剂量和重复注射分别比低剂量和单次注射后产生更高的HAL注射后的RHAL/HAL比值和更低的RHAL注射后的HAL/RHAL比值。与精神分裂症患者的结果相比，豚鼠中从HAL到RHAL的转化大于人类，但豚鼠和人类之间的反向转化似乎相似。基于RHAL/HAL比值的剂量依赖性增加，提出了HAL治疗的治疗窗效应假说。
