The Assessment of the Correlation between Nortriptyline Clearance and Metoprolol Metabolic Ratio

Nortriptyline 청소율과 Metoprolol 산화대사능과의 상관관계

Background: The wide interindividual differences in the responsie of nortriptyline following conventional dose is well documented. Nortriptyline is mainly metabolized by 10-hydroxylation, which accounts for about 70% of dose recovered in urine as free or conjugated forms. The 10-hydroxylation of nortriptyline is suggested to be catalyzed by debrisoquin 4-hydroxylase(CYP2D6) from the result of in vitro and in vivo studies. Metoprolol is metabolized via CYP2D6 to ${\alpha}-hydroxymetoprolol$, and the ratio of metoprolol and ${\alpha}-hydroxymetoprolol$ is used as an index of metabolic capacity of CYP2D6. By assessing the correlation between metoprolol metabolic ratio(MR) and nortriptyline clearance, we want to confirm the genetic control mechanism of the major metabolic pathway of nortriptyline in vivo. Method: Fifteen healthy, unrelated, male volunteers participated in the study. They were phenotyped for individual ability to hydroxylate metoprolol before single dose pharmacokinetic study of nortriptyline. Venous blood samples were collected serially after oral administration of a single dose of either 25 or 50mg nortriptyline($Sensival^{\circledR}$) and plasma concentration of nortriptyline was measured by HPLC method. Plasma concentration-time data of nortriptylinem was analyzed by non-compartmental method. Results: The mean values of metoprolol MR and nortriptyline clearance of 15 tested subjects were $1.93{\pm}2.02$ and $55.37{\pm}30.28$ L/hr, respectively. The nortriptyline clearances were well correlated $({\gamma}_s=-0.84,\;p<0.01)$ with the metoprolol MR values. Conclusion: The correlation between the metoprolol MR values and nortriptyline clearances provides a strong evidence that the hydroxylation of nortriptyline and metoprolol is under the same genetic or cosegregated control.

연구배경 : 유전적 다형성을 갖는 CYP2D6의 활성도를 알아보는 표지약물로 metoprolol을 이용하여 in vivo에서 metoprolol의 metalolic ratio와 삼환계 항우울제인 nortriptyline의 청소율간의 상관성을 검토함으로써 nortriptyline의 주대사 경로를 관장하는 산화효소계가 CYP2D6임을 확인하고자 하였다. 방법 : 친척관계가 없는 15명의 건강한 성인 남자(나이 $25{\pm}3.02$세, 체중 $66.9{\pm}10kg$; 평균 ${\pm}$표준편차)를 대상으로 하였다. Nortriptyline 약동학 시험전 100mg의 metoprolol tartrate를 1회 경구복용시켜 8시간 요중 배설되는 metoprolol과 ${\alpha}-hydroxymetoprolol$의 비로서 CYP2D6효소의 산화대사능 지표로 삼았다. Nortriptyline 혈장농도측정을 위해 약물투여후 72시간까지 정맥혈을 채혈하고 HPLC을 이용하여 약물농도를 측정하였으며 혈장농도-시간의 데이타를 noncompartment 약동학적 방법을 이용해 분석하였다. 결과 : 15명의 피험자의 평균 metoprolol MR과 nortriptyline 체내 청소을은 각각 $1.93{\pm}2.02$과 $55.37{\pm}30.28L/hr$이었다. Metoprolol MR 값은 nortriptyline의 체내 청소율과 밀접한 상관관계$({\gamma}_s,=-0.84,\;p<0.01)$를 보였다. 결론: Metoprolol의 산화대사능 값과 nortriptyline의 체내 청소율 값의 밀접한 상관관계는 nortriptyline의 대사는 간내 microsome 산화효소계중 CYP2D6의 활성도에 의해 좌우됨을 시사하였다.