Pharmacokinetic Analysis on Autoinduction of Carbamazepine Metabolism

Carbamazepine 자가대사유도의 약동학적 분석

  • Yoon, Young-Ran (Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Cha, In-June (Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Kim, Kyung-Ah (Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Shim, Joo-Chul (Department of Psychiatry, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Kim, Young-Hoon (Department of Psychiatry, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Shin, Jong-Beom (Department of Pediatrics, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital) ;
  • Shin, Jae-Gook (Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital)
  • Published : 1996.12.30

Abstract

Background : The time course and the extent of the autoinduction of carbamazepine(CBZ) were evaluated in Korean, using various methods to measure CBZ autoinduction. Method : Two phases of pharmacokinetic studies were peformed in 12 normal healthy volunteers, one after single 400mg dose of CBZ and other after multiple 200mg/day dose for 2 weeks, with 2 week washout period between two phases. Serial blood samples were drawn upto 96 hours and unine samples were collected in each phase, and daily trough CBZ levels were measured during multiple doses of CBZ. CBZ and its metabolites, CBZ-10,11-epoxide(CBZ-E) and trans-CBZ-10,11-diol(trans-CBZ-diol) concentrations were determined with HPLC and their ratios were used to evaluate CBZ autoinduction. Results : During multiple administration of CBZ 200mg, daily trough CBZ concentration was decreased till 2 weeks after dose, and actual CBZ $concentration(2.8\;{\mu}g/ml)$ was 53.9% of predicted level simulated under the assumption without the autoinduction. Total CBZ clearance measured after multiple dose(35.1ml/h/kg) was significantly greater than that of single dose study(21.1ml/h/kg), and half-life of CBZ was shortened from 48.3 hours in initial dose to 27.0 hours in consecutive multiple doses(p<0.01). AUC ratios of CBZ-E/CBZ and trans-CBZ-diol/CBZ were significantly increased during multiple does administration from 0.09 and 0.07 to 0.15 and 0.13, respectively. The per-percent increase of 24 hour percent urinary excretion of CBZ-E(260.7%) and trans-CBZ-diol(804.3%) showed significant differences compared to that of CBZ(48.3%) between single and multiple dose studies(p<0.01). Conclusion : From these results, multiple administration of CBZ seems to develop the autoinduction of CBZ significantly in Korean, and the time course and the extent of the CBZ autoinduction should be considered for determining optimum CBZ dosage, especially when CBZ is administered initially or the dosage is changed.

연구배경 : CBZ의 자가대사유도를 평가하는 다양한 방법들을 이용하여 한국인에서 CBZ의 자가대사유도 및 그 정도를 평가하였다. 방 법 : 동일한 피험자에 400mg의 CBZ을 경구로 1회 투여 후 약동학적 연구를 시행하고 2주간의 휴약기간을 거친후 다시 일일 200mg의 CBZ을 2주간 반복 투여하면서 CBZ의 일일 최저농도의 변화를 관찰하고 최종투약 후 다시 약동학적 연구를 시행하는 방법으로 진행하였으며, 이 과정에서 혈액 및 뇨의 CBZ 및 대사산물들을 측정하여 각각 약동학적 분석을 시행하고 이로부터 1회 투여시와 반복투여시의 결과를 비교 분석하였다. 결 과 : CBZ 200mg을 반복투여시 자가대사유도로 인한 일일 최저 혈장 CBZ의 농도감소는 2주 후까지 지속되었으며 이때 측정된 CBZ 농도는 대사유도가 없다는 가정하에 예측되는 농도의 53.9%에 불과하였다. 반복투여 후 CBZ의 청소율은 1회 투여후의 평균 21.1ml/h/kg에서 35.1ml/h/kg로 증가하였으며 소실반감기는 평균 48.3 시간에서 27.0시간으로 현저히 감소하였다(p<0.01). CBZ-E/CBZ 및 trans-CBZ-diol/CBZ의 AUC 비는 각각 평균 0.09 및 0.07에서 0.15 및 0.13으로 현저히 증가하였으며, 24시간 뇨로 배설된 투여 용량 기준 CBZ-E 및 trans-CBZ-diol의 양은 1회 투여시에 비해 반복투여시 각각 260.7 및 804.3%씩 증가하여 CBZ의 증가율 48.3%와는 현저한 차이를 보였다(p<0.01). 결 론 : 이상의 연구결과는 한국인에서 CBZ의 자가대사유도가 현저하게 발생함을 제시하고 있으며, 따라서 CBZ 투약 초기 및 용법의 변경시에는 자가대사유도의 시기 및 그 정도를 고려한 적정약물용법의 조정이 필요할 것으로 사료된다. 감사의 글 : 약물농도 측정과정에서 필요한 CBZ-E 및 trans-CBZ-diol의 표준물질을 제공해주신 한국 썰 시바-가이기에 감사를 드립니다.

Keywords