藥學雜誌電子報99期
105
Vol. 26 No. 4
Dec. 31 2010
中華民國九十九年十二月三十一日出版

葡萄柚汁與藥物的交互作用的新認知


雲林長庚紀念醫院藥劑科藥師 林嘉慶

摘要

食物與藥物的交互作用在多年前就已經被注意了,而其中最廣為大家所知的便是葡萄柚汁與藥物間的交互作用;近年來由於新的藥動學技術與更多的臨床證據下,對葡萄柚的交互作用有了新的認知;其中常被提到不可與葡萄柚汁併用的鈣離子阻斷劑,僅felodipine被認為會實質上造成臨床影響,因此felodipine不能與葡萄柚汁併用,其他的鈣離子阻斷劑是可以與葡萄柚汁併用的。本文將以實證及臨床的方面來討論及更新多種藥物與葡萄柚汁交互作用,並以表格方面呈現許多結果,方便讀者的應用。

關鍵字: 葡萄柚汁、鈣離子阻斷劑、藥物交互作用、cytochromes P450、grapefruit juice、calcium channel blocker

壹、前言

由於葡萄柚汁富含維他命C、纖維素、鉀離子且低熱量,因此在國外可是非常流行健康食品,也因此被美國心臟協會列為推荐的食品。然而在西元1989年,人們開始注意到某些藥品與葡萄柚汁一起使用會增加藥品的效果,有些藥品甚至會增加2~3倍的血中濃度1。這個交互作用的發現主要是因為當初為了測試酒精與藥物的交互作用時,以葡萄柚汁來當作矯味劑時,才被發現的。也由於這個發現,引起許多學者開始進一步著手研究葡萄柚汁與藥物之間的交互作用。本文亦針對想繼續使用葡萄柚汁的病人提出一些開立處方建議,讓病人可以不用因為需要服藥而改變生活型態。

貳、藥理學機轉

藥品在人體的代謝主要是經由肝臟cytochrome P450系統,因此只要是干擾cytochrome P450系統的藥品,便有可能會與其他藥品有交互作用2。然而葡萄柚汁與藥物之間的交互作用又是與常見的藥物交互作用不同,葡萄柚汁裡的成分主要是抑制遠端小腸黏膜上的CYP 3A system (主要指CYP 3A4和3A5);大部分口服藥物便是在小腸這個部位吸收進入全身循環,因此在此抑制了藥物的代謝便會增加藥物的身體可用率,如圖一所示。葡萄柚汁的成分中以furanocoumarins這類最易影響到小腸的CYP 3A system3。至於一般人每日飲用8~12oz的葡萄柚汁時,CYP 3A system濃度將在4小時之內減少47%,效果可能維持至少24小時,大約要72小時才可以完全恢復原有的CYP 3A system濃度4-5

圖一 口服藥物與葡萄柚汁交互作用流程圖

 

基於以上的概念,歸納出三點會與葡萄柚汁產生交互作用的必要條件:(1)併用藥物須是由CYP3A代謝。(2)併用藥物是為口服使用。(3)併用藥物的身體可用率非100%且進入全身循環前會被腸道CYP3A所代謝。

參、藥物交互作用的實驗設計

以實驗室數據(area under the plasma concentration-time curve, AUC)來代表藥物在體內的藥動學參數,AUC0代表對照組,為單一藥物的AUC;AUC1為實驗組,為藥物和葡萄柚汁合併使用時的AUC。最後以AUC ratio評估兩個藥品是否具有藥動學上的交互作用6:(1)Equation 1: AUC ratio = AUC1 / AUC0。(2)當ratio = 1,表示無交互作用;ratio < 1,表示為酵素誘導(enzyme induction);ratio > 1,表示為酵素抑制(enzyme inhibition);如表一所示。

表一 藥動學上對酵素抑制程度的解釋6

Categorization of inhibitory drug interactions

AUC ratio

Description of inhibition

>1.25

Negligible

≧1.25 and <2.0

Weak

≧2.0 and <5.0

Moderate

≧5.0

Strong

 

肆、統計與臨床上的意義

由於藥動學上的交互作用最後不一定會造成臨床上病人療效的差異,因此要評斷臨床上的交互作用就得參考exposure - response relationship,即藥效學上的評估了。譬如同一個AUC ratio在不同藥品上,所代表的臨床意義將會不同。例如:若AUC ratio = 1.5發生在一般的NSAIDs上,將不被認為是一個重要的交互作用;但若發生在治療範圍狹窄的藥物上,如warfarin,將被認為是一個重要的交互作用,而且須建議避免同時使用。

一、藥動學與藥效學評估結果

表二中依交互作用的嚴重程度歸納出三類7:(1)Category A:交互作用在臨床上幾乎可以忽略。病人是可以正常飲用葡萄柚汁,無須擔心交互作用。(2)Category B:交互作用是有可能發生的。但不需要刻意避免葡萄柚汁的使用;唯需注意藥物的療效是否有增加。(3)Category C:統計上確實會造成藥物交互作用。基於安全的考量就必須避免葡萄柚汁的使用或是改用同類藥中較少交互作用者。

因此表二、表三中列出各類藥物交互作用的嚴重程度,可以給予臨床作業者提供一些參考。表中需要注意的是,常用的鈣離子阻斷劑中僅felodipine被列在Category C,基本上是不可與葡萄柚汁併用的;至於其他常用的鈣離子阻斷劑則都是Category A,可以正常飲用葡萄柚汁;另外需注意的是在抗憂鬱藥中buspirone與降血脂藥的simvastatin也都是Category C。有了以上的原則,我們可以簡單的記住felodipine、buspirone、simvastatin都是不可與葡萄柚汁併用的。如此可以讓藥師在臨床服務上更有效率。

表二 藥物與葡萄柚汁交互作用的臨床意義7

Summary of prescription drug interactions with grapefruit juice categorized based on likelihood of clinical importance

Category A

Low or negligible likelihood of clinically important interaction

Category B

Clinically important interaction possible

Category C

Clinically important interaction likely

Macrolide antimicrobials

clarithromycin

erythromycin

telithromycin

 

 

Sedative-hypnotics and anxiolytics

alprazolam

triazolam

buspirone

quazepam

midazolam

 

 

diazepam

 

Other psychotropics drugs

clozapine

 

 

fluvoxamine

   

 

haloperidol

 

 

methadone

 

 

sertraline

 

 

Calcium channel antagonists

amlodipine

nisoldipine

felodipine

diltiazem

 

 

nicardipine

 

 

nifedipine

 

 

nimodipine

 

 

verapamil

 

 

Antiarrhythmics

amiodarone

 

 

quinidine

 

 

Statins

atorvastatin

lovastatin

simvastatin

pravastatin

 

 

Anticonvulsants

phenytoin

carbamazepine

 

Immunosupressant

 

Cyclosporine

 

Antiretrovirals

amprenavir

 

 

indinavir

 

 

saquinavir

 

 

Hormones

ethinylestradiol

 

 

17β-eatradiol

 

 

prednisone

 

 

methylprednisolone

 

 

l-thyroxine

 

 

Other drugs

acebutolol

 

 

digoxin

 

 

glyburide

 

 

omeprazole

 

 

scopolamine

 

 

sildenafil

 

 

註:1. 少用藥品,如:antimalarial and antiparasitic、以及下市的藥品和在美國無許可證的藥品都沒有納入這個表格。另外葡萄柚汁(正常濃度)飲用量為每日8~12 oz。

2. 此表主要是由人體試驗的藥動學資料衍生而來,因此可當作較具有實證的資料。

 

表三 藥物交互作用的實證4-5

Key recommendations for practice

Clinical recommendation

Evidence

rating

Comments

Patients should discontinue grapefruit

consumption for 72 hours before use of a drug that may interact with it.

c

The potential for a grapefruit-drug interaction persists for up to 72 hours according to one study.

Potential grapefruit-drug interactions cannot be avoided by separating times of medication administration and grapefruit consumption.

c

Studies have shown that consuming 8 oz of grapefruit juice may decrease the concentration of intestinal cytochrome P450 3A4 by 47 percent for 24 to 72 hours.

 

 

表四為臨床上使用時的開方指引,對於有可能造成藥物交互作用的藥品,都會列出建議的替代用藥。對於一般的藥師則可專注在antiarrhythmics、calcium channel blockers、statins此三類常用的藥品,對於這三類藥品的替代用藥可以多加詳記,以方便在臨床上的應用。

表四 臨床上併用時的對策,使用較少交互作用的取代藥8-9

Grapefruit-Drug interactions and alternative therapies

Drug class

Drugs potentially

affected by grapefruit

Effects of interaction

Alternative treatments

antiarrhythmics

amiodarone disopyramide

quinidine

Increased plasma concentrations of

amiodarone may cause thyroid or pulmonary toxicity, liver injury, QTc prolongation, proarrhythmic disorders,

and bradycardia.

digoxin

diltiaze

verapamil

Beta blockers

Increased plasma concentration of quinidine and disopyramide may be cardiotoxic causing torsades de pointes.

Calcium channel

blockers

felodipine

nicardipine

nifedipine

nimodipine

nisoldipine

Increased plasma concentration may lead to flushing, peripheral edema, headaches, tachycardia, symptomatic hypotension, and myocardial infarction in rare cases.

amlodipine

diltiazem

verapamil

Statins

atorvastatin

lovastatin

simvastatin

Increased plasma concentration may cause headaches, gastrointestinal complaints, hepatic inflammation, and myopathies.

fluvastatin

pravastatin

rosuvastatin

fibric acids

nicotinic acid

bile acid sequestrants

Immunosuppressants

cyclosporine

tacrolimus

Increased drug exposure without effects on peak concentration may cause increased adverse events or toxicity evidenced by renal toxicity, hepatic toxicity, and increased immunosuppression.

No alternatives available

Protease inhibitors

saquinavir

Increased plasma concentrations may

cause increased side effects such as headache, fatigue, insomnia, and anxiety.

amprenavir

atazanavir

fosamprenavir

indinavir

iopinavir/ritonavir

nelfinavir

ritonavir

 

伍、結論

葡萄柚汁的交互作用在臨床上雖然已被注意很久,但藉由更新的資料佐證,我們可以提供給病人更多的選擇,而不是一昧的要求病人停止使用葡萄柚汁。對於醫院的其他工作夥伴,我們可以提供更多、更確切的資料讓臨床醫師有更多的選擇。對於藥師同仁而言更精簡的資料,不僅可以提高資料的應用性,也可以降低藥師的負擔。

參考資料:

1. Bailey D, Spence J, Edgar B, Bayliff C, Arnold J. Ethanol enhances the hemodynamic effects of felodipine. Clinical and investigative medicine. Medecine Clinique et Experimentale. 1989; 12(6): 357.

2. Guengerich F. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annual Review of Pharmacology and Toxicology. 1999; 39(1): 1-17.

3. Schmiedlin-Ren P, Edwards D, Fitzsimmons M, et al: Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metabolism and Disposition. 1997; 25(11): 1228.

4. Takanaga H, Ohnishi A, Murakami H, et al: Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clinical Pharmacology & Therapeutics. 2000; 67(3): 201-214.

5. Lundahl J, Regardh C, Edgar B, Johnsson G. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. European Journal of Clinical Pharmacology. 1995; 49(1): 61-67.

6. Greenblatt D. Preparation of scientific reports on pharmacokinetic drug interaction studies. Journal of Clinical Psychopharmacology. 2008; 28(4): 369.

7. Mertens-Talcott S, Zadezensky I, De Castro W, Derendorf H, Butterweck V. Grapefruit-drug interactions: can interactions with drugs be avoided? The Journal of Clinical Pharmacology. 2006; 46(12): 1390.

8. Bailey D, Dresser G. Interactions between grapefruit juice and cardiovascular drugs. American Journal of Cardiovascular Drugs. 2004; 4(5): 281-297.

9. Libersa C, Brique S, Motte K, et al: Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. British Journal of Clinical Pharmacology. 2000; 49(4): 373.

 

Update on Drug Interactions with Grapefruit Juice

Chia-Ching Lin
Department of Pharmacy, Chang Gung Memorial Hospital, Yunlin Branch

Abstract

The interactions between drugs and foods have been mentioned many years ago, and grapefruit juice is the most well-known of these foods. According to the recent pharmacokinetic research and clinical evidence in recent years, there're some new perceptions of the interaction between grapefruit juice and medicines. The famous examples that cannot combine with grapefruit juice are calcium channel blockers, but only felodipine with grapefruit juice can result in clinical effect. According to this reason, felodipine cannot combine with grapefruit juice; other calcium channel blockers will not be limited. This article will discuss and update the interaction of grapefruit juice based on evidence and clinical issue, and the result will be represented by tables which are convenient for readers to utilize.