Pharmacokinetic Study of Isoniazid and Rifampicin in Healthy Korean Volunteers

정상 한국인에서의 Isoniazid와 Rifampicin 약동학 연구

Background : Isoniazid(INH) and rifampicin(RFP) are potent antituberculous drugs which have made tuberculous disease become decreasing. In Korea, prescribed doses of INH and RFP have been different from those recommended by American Thoracic Society. In fact they were determined by clinical experience rather than by scientific basis. Even there has been. few reports about pharmacokintic parameters of INH and RFP in healthy Koreans. Method : Oral pharmacokinetics of INH were studied in 22 healthy native Koreans after administration of 300 mg and 400mg of INH to each same person successively at least 2 weeks apart. After an overnight fast, subjects received medication and blood samples were drawn at scheduled times over a 24-hour period. Urine collection was also done for 24 hours. Pharmacokinetics of RFP were studied in 20 subjects in a same fashion with 450mg and 600mg of RFP. Plasma and urinary concentrations of INH and RFP were determined by high-performance liquid chromatography(HPLC). Results : Time to reach peak serum concentration (Tmax) of INH was $1.05{\pm}0.34\;hrs$ at 300mg dose and $0.98{\pm}0.59\;hrs$ at 400mg dose. Half-life was $2.49{\pm}0.88\;hrs$ and $2.80{\pm}0.75\;hrs$, respectively. They were not different significantly(p > 0.05). Peak serum concentration(Cmax) after administration of 400mg of INH was $7.14{\pm}1.95mcg/mL$ which was significantly higher than Cmax ($4.37{\pm}1.28mcg/mL$) by 300mg of INH(p < 0.01). Total clearance(CLtot) of INH at 300mg dose was $26.76{\pm}11.80mL/hr$. At 400mg dose it was $21.09{\pm}8.31mL/hr$ which was significantly lower(p < 0.01) than by 300mg dose. While renal clearance(CLr) was not different among two groups, nonrenal clearance(CLnr) at 400mg dose ($18.18{\pm}8.36mL/hr$) was significantly lower than CLnr ($23.71{\pm}11.52mL/hr$) by 300mg dose(p < 0.01). Tmax of RFP was $1.11{\pm}0.41\;hrs$ at 450mg dose and $1.15{\pm}0.43\;hrs$ at 600mg dose. Half-life was $4.20{\pm}0.73\;hrs$ and $4.95{\pm}2.25\;hrs$, respectively. They were not different significantly(p > 0.05). Cmax after administration of 600mg of RFP was $13.61{\pm}3.43mcg/mL$ which was significantly higher than Cmax($10.12{\pm}2.25mcg/mL$) by 450mg of RFP(p < 0.01). CLtot of RFP at 450mg dose was $7.60{\pm}1.34mL/hr$. At 600mg dose it was $7.05{\pm}1.20mL/hr$ which was significantly lower(p < 0.05) than by 450mg dose. While CLr was not different among two groups, CLnr at 600 mg dose($5.36{\pm}1.20mL/hr$) was significantly lower than CLnr($6.19{\pm}1.56mL/hr$) by 450mg dose(p < 0.01). Conclusion : Considering Cmax and CLnr, 300mg, of INH and 450mg RFP might be sufficient doses for the treatment of tuberculosis in Koreans. But it remains to be clarified in the patients with tuberculosis.

연구배경 : Isoniazid(INH)와 Rifampicin(RFP)은 강력한 항결핵효과를 가지고 있어 결핵치료에 없어서는 안되는 중요한 약제이지만 우리나라에서는 미국흉부학회에서 추천하는 용량과 다른 용량을 흔히 처방하면서도 적절한 용량에 대한 평가는 미흡하여 결핵의 치료에 혼선을 초래하고 있는 실정이다. 이에 저자들은 정상 한국인에서의 INH, RFP 각각의 약물동력학을 먼저 알아보고, INH 300mg과 INH 400mg복용시, RFP 450mg과 600mg복용시 약통학(pharmacokinetics)적 변화를 비교 분석함으로써 한국인에서 INH, RFP 처방의 기초자료로 제공하고자 본 연구를 시행하였다. 방 법 : 정상인 자원자 22명을 12시간 이상 금식시킨 후 INH 300mg을 복용하게 한 다음, 시간경과에 따른 INH 혈중농도 및 INH 뇨배설량을 High-performance liquid chromatography(HPLC)를 이용하여 측정하였다. 2주후 동일인을 대상으로 INH 400mg을 복용시킨 다음 같은 방법으로 INH 혈중농도 및 뇨배설량을 측정하였다. 마찬가지 방법으로 자원자 20명을 대상으로 RFP 450mg과 600mg을 2주 간격으로 복용시킨 다음, 시간경과에 따른 RFP 혈중농도 및 뇨배설량을 측정하였다. 이 결과를 토대로 최고혈중농도(peak serum concentration, Cmax), 최고혈중농도 도달시간(time to reach to peak serum concentration, Tmax), 혈중반감기, 소실속도상수(elimination rate constank, Ke), 전신 클리어런스(total clearance, CLtot), 신 클리어런스(renalclearance, CLr) 및 신외 클리어런스(nonrenal clearance, CLnr)를 계산하여 비교하였으며, paired t-test로 p value < 0.05 일 경우 통계적으로 의미있는 차이가 있는 것으로 판정하였다. 결 과 : 1) INH 결과 ㄱ) Tmax는 INH 300mg군이 $1.05{\pm}0.34$시간, INH 400mg군이 $0.98{\pm}0.59$시간으로서 두 군간에 차이가 없었고(p > 0.05), 혈중반감기도 INH 300mg군이 $2.49{\pm}0.88$시간, INH 400mg 군이 $2.80{\pm}0.75$시간으로서 두 군간에 차이는 없었다(p>0.05). ㄴ) Cmax는 INH 300mg군이 $4.37{\pm}1.28mcg/mL$, INH 400mg군이 $7.14{\pm}1.95mcg/mL$로서 INH 400mg군에서 유의하게 높았지만(p < 0.01), Ke는 각각 $0.30{\pm}0.07hrs^{-1}$, $0.27{\pm}0.11hrs^{-1}$로서 차이가 없었다(p < 0.05). ㄷ) CLtot은 INH300mg군이 $26.76{\pm}11.80mL/hr$, INH 400mg군이 $21.09{\pm}8.31 mL/hr$로서, INH 400mg군에서 유의하게 낮았다(p < 0.01). 이중 CLr은 각각 $3.04{\pm}1.68mL/hr$, $2.91{\pm}0.77mL/hr$로서 두 군간에 차이가 없었으나(p>0.05), CLnr은 각각 $23.71{\pm}11.52mL/hr$, $18.18{\pm}8.36mL/hr$로서 INH 400mg군에서 유의하게 낮았다(p<0.01). 2) RFP결과 ㄱ) Tmax는 RFP 450m군이 $1.11{\pm}0.41$시간, RFP 600mg군이 $1.15{\pm}0.43$시간으로서 두 군간에 차이가 없었고(> 0.05), 혈중반감기도 RFP 450mg군이 $4.20{\pm}0.73$시간, RFP 600mg군이 $4.95{\pm}2.25$ 시간으로서, 두 군간에 유의한 차이는 없었다(p > 0.05). ㄴ) Cmax는 RFP 450mg군이 $10.12{\pm}2.25mcg/mL$, RFP 600mg군이 $13.61{\pm}3.43mcg/mL$로서 RFP 600mg군에서 유의하게 높았고(p < 0.01), Ke도 각각 $0.17{\pm}0.03hrs^{-1}$, $0.15{\pm}0.03hrs^{-1}$로서 RFP 600mg군에서 통계적으로 유의하게 낮았다(p < 0.01). ㄷ) CLtot은 RFP 450mg군이 $7.60{\pm}1.34mL/hr$, RFP 600mg군이 $7.05{\pm}1.20mL/hr$로서, RFP 600mg군에서 유의하게 낮았다(p < 0.05). 이중 CLr은 각각 $1.41{\pm}0.65mL/hr$, $1.69{\pm}0.61mL/hr$로서 두 군간에 차이가 없었으나(p>0.05), CLnr은 각각 $6.19{\pm}1.56mL/hr$, $5.36{\pm}1.26mL/hr$로서 RFP 600mg군에서 유의하게 낮았다(p < 0.01). 결 론 : 한국인에서는 INH는 300mg이, RFP은 450mg이 적절한 일일용량으로 생각되나 이는 향후 복합적으로 결핵약을 복용하는 실제 결핵환자를 대상으로 한 추시가 필요할 것으로 생각된다.