w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No. 2. 2006 y w w CÁ«Ÿ B { BÁ B û w w w w C t t t sƒ The Effect of Food on Absorption of Drug in the Gastrointestinal Tract Hwi-yeol Yun a, Min-sun Baek b, Kwang-il Kwon a a College of Pharmacy, Chungnam National University, Daejeon, Korea b Korea Food and Drug Administration, Seoul, Korea Drugs are often taken together with meals and there are numerous opportunity for food-drug interaction to occure. Food-drug interactions and their clinical consequences are very complex indeed. The composition of the meal, and the volume of fluid that is ingested often are decisive factors in food-drug interactions. Various formulations of a specific drug may behave differently. Solutions and suspensions seem to be less susceptible and enteric-coated preparations are more susceptible, to food interactions than are other dosage forms but exceptions to this rule do exist. Furthermore, generic and environmental factors, disease and other drugs cause considerable inter- and intraindividual variation in food-drug interactions. Also, eating habits are dissimilar in different parts of the world, and diets often vary greatly from day to day. The taking of drugs together with meals offers some obvious benefits. It may help to reduce gastrointestinal irritation and compliance is improved. On the other hand, in some cases food interferes seriously with drug absorption. The purpose of this review is to clarify the complexity of food-drug interactions, and to discuss interactions that may be of clinical importance. Key wordsg food-drug interaction, drug absorption, Food-effect w mw n x p p mw yx mw y z ƒ ùkù. 1) n y mw e x. 2) w y m w w j ƒ ù Áyw p w w d. 3) Áyw p w w pka, w n š p w j w. w d Áyw w w n y x k n d w ƒ j w Correspondence to : «Ÿ û w w w w Ÿ ª 220 û w w w 405y Tel: 042-821-5937, Fax: 042-823-6781 E-mail: kwon@cnu.ac.kr. ƒ w d 4) y ƒ j w. 5) w y d ƒ y ƒ. y d w w š, w ƒ,, ú. w w d ƒ w yw» z x dw. w w x y e z w ƒ. e (therapeutic range) j w e e ƒ w w w ùkü ù e z ƒ ùkù. 6) w ùkú y y w wš w y w w w œwš w. 147
148 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 FOUFSBM mw w mw w ù y» k» w d (Physiological factor) p w yw (Physicochemical factors of drugs) ƒ ù. 3) ƒ Áyw p w š w j, y ƒ w. d w y w w» w. 1) y ü m. m w w. ü (gastric emptying time) ü m (rate) ƒ w. œ q(slow wave)ƒ w w ù. ƒ p (gastrin) pg (acetylcholine) q s q w y w. w ƒ p (gastrin) p g (acetylcholine) ƒ ƒ w. s w (pylorus) w w ü ƒ. w ü. MMC(Migrating Motor Complex)»»y ¾ j w. MMC w y ü. ü v,,, n, w w w yw. t 1 ü w w y ùkü. 2) y ü ph ü ph ù j w œ ph 1-2 š, z 3.5-5.0¾ w. w ph y j w. ƒ ph- ƒ (ph-partition theory)». w x w x w š, w mw. w y pka wwš ( x ) ph. 7) :» : [ HA] pka = ph + log ------------- A [ ] pka = BH + [ ] ph + log --------------- [ B ] [HA], [B] : yx [A - ], [BH + ] : yx ph( 1-3) ƒ pka û k w ƒ m w. w x ü ph( 7.4) w w s m w w x ü w. Brodie š w pkaƒ 4» w de eƒ e w. 8) ù m w z w ph- ƒ. ph- ƒ w l j» ƒ j ùkù w w.» ƒ ph- ƒ w. w de eƒ ew ƒ. t ph œ w. t ph ü phƒ 7.2 Table 1. Factors of gastric emptying time Factors Volume Temperature Viscosity and Osmotic pressure Administration of Glipid or fatty acid Drug administration Body position Change of gastric emptying time Volume increase : faster Temperature increase : delay Viscosity and Osmotic pressure increase : delay delay Metoclopramide, Cisapride : fasterg Ethanol, Acetaminophen, diphenhydramine : delay Lie in right side : faster
y w w 149 w t ph 6.1-6.8 d x t ph(virtual ph) š w. t ph» y w x Na + /H w + t + H t ge (glycocalyx) w ƒ. ge ƒ y w t ph ü w w, ge d (unstirred water layer, d(stagnant layer), y d(aqueous diffusion layer) w y w w. ph- w wš. y ü ph t ph(virtual ph) w. 3) y ü x x n s m w w w. x s sx k w. n ƒ j s n x sx k w e ƒ.(perfusion rate limited) s n ƒ s n w x w l ¼ w s. x x ƒ. w n ƒ û x w w n ƒ w.(diffusion rate limited) n ƒ s m w ƒ w. 10) 1 x ùkü tritiated-water ph- š s w œ (aqueous pore) m w s n ƒ. x w ƒw ribitol n ƒ x ƒ w. 11) 4) y ü z w n y m w z w. w w z y sw š Fig. 1. Change of drug absorption rate for blood flow in GI tract (þ: Tritiated water, ý: Ethanol, ù: Urea, ø: Ribitol). y n z m z (first-pass effect) ƒ. v s t z cytochrome P450 3A4(CYP3A4) z,» w w. CYP3A4 w m. š MDR protein substrate w CYP 3A4» w. cyclosporin A MDR protein w efflux wƒ ùš, s Á efflux CYP 3A4 ¼ ƒ. š CYP3A4 MDR protein w efflux cyclosporin A w. w MDR protein CYP3A4 y w w w n cyclosporin A û š š.( 2) Fig. 2. Effect of drug absorption and metabolism for MDR protein in GI mucous cell
150 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 Fig. 3. Potential rate-limiting steps in drug absorption processes after oral administration of solid dosage forms such as tablets or capsules Fig. 5. Plasma concentration after 1g griseofulvin single oral administration (þ: High-fat meal. ý: High-protein meal, ù: Fasted state) w. w ƒ ù ƒ w w. 12,13) Fig. 4. Plasma concentration after 500mg erythromycin single oral administration (þ: Fasted state with water 250ml. ý: Fasted state with water 20ml, ù: Fed-state only lipid, ø: Fed-state only carbohydrate, : Fed-state only protein) w 400 ü w. ü Ester amides ƒ w, w, nitro, diazo y, dehydroxylation, dealkylation, deamination, acetylation, esterification w. ü w n w z. ƒ z wš z w ƒ ù» w ü 5) MDR protein MDR protein(multidrug resistence protein) p-glycoprotein v s w efflux rv. MDR protein s n w ü ü w w.» s š, w s n w efflux sƒ w w ü ùkü x. w v (log D) w d ƒ» x ü. w MDR protein» w t cyclosporin Aƒ n ƒ MDR protein w w ƒ. 6) w 3 šx ùkü. šx n z w (dissolution) n (permeation) ƒ Table 2. Factors of dissolution rate Factors Changes of the dissolution rate Example Particle size Small particle size: dissolution rate increase Griseofulvin, Spironolactone Polymorphism Meta-stable form: dissolution rate increase Chloramphenicol, Barbiturate derivertives Amorphous Dissolution rate increase Novobiocin, Insulin-Zn Solvation Anhydrate: dissolution rate increase Ampicilin, Caffeine, Theophylline Salt Dissolution rate increase Tolbutamide, Phenobarbital
y w w 151 Table 3. Effect of food on drug absorptions Decrease Delay Increase Ampicillin Acetaminophen Acitretin Aspirin Aspirin Cholorothiazide Atenolol Cephalosporin Diazepam Captopril Diclofenac Dicoumarol Ethanol Digoxin Diftalone Hydrochlorothiazide Furosemide Griseofulvin Iron Indoprofen Labetalol Levodopa Nitrofurantin Metoprolol Penicillins Sulfadiazine Nitrofurantoin Sotalol Sulfaisoxazole propranolol Tetracyclin Valproate Riboflavin w ƒ n w (rate-limiting) w ƒ w. ù w ƒ w. w w t 2 w. 7) n (Permeation rate) w ƒ w w s n w. n w tx. Permiation rate = P iás iác i Pi : n (Permiability), Si : n w t, Ci : ü n n, n w t, w ƒw. n (permeability) w ƒ w. Á (Lipophilicity) Á j»(molecular size) Á w(charge) ƒ jš, s n w w j» ƒ x s n. w w w w w w y ü y Áyw p w š w w dw. w w, ƒ z š, t 3 w yw t. 12~16) 1) ü k. ü w ùkù w (penicillin, erythromycin ) ü w w w ƒ w. w v sy w ƒ ƒ. š ü w»š šx w. š y w y y w y ü ƒ ƒ w y ƒ. 2) ph y ph- w ph y j w e. w ph- w w ph Áyw p š w y y mw y k. ü ph y, w w yw. w y w w w ƒ. 4 erythromycin stearate, k y z, œ 240 ml, œ 20 ml w z n w x š. 17) Erythromycin w n w û y w. w œ 20ml wì n w š x w w ü œ w phaseƒ z n w ƒw. Erythromycin 240ml wì w ƒ w y w w w š ü z ƒ. 3) w. ƒ w ƒ y ƒ. ü y w ù w w ƒ g. š w ƒw. 18)
152 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 w» e» ww n w w yw ù. Fig. 6. Plasma concentration after 250 mg fenofibrate SR capsule single oral administration (þ: 900Kcal, 30% fat contained high caloric, fat meal. ý: 700Kcal, 20% fat contained standard caloric, fat, ù: Fasted state) 7 š, š w z grisseofulvin n w x y š. š y w j š griseofulvin ƒ y g ƒ k. w š œ n w j ƒ. 19) 6 e w n w z fenofibrate e n w z x š. 20,21) 900Kcal, 30% w w 700Kcal, 20% w w w z n w e w w w w y w. š wì w ƒw ü y š w œ y yƒ y w š w w ƒ ƒw ƒ» w ƒ. Fig. 7. Plasma concentration after 10mg felodipine single oral administration with grape fruit juice (þ: Pretreated with grape fruit juice on 3 times a day for 5 days, ý: administered with grape fruit juice on 8 ounce, ù : administered with water) 4) ü x ƒ ü x ƒ w. ƒ x s»» j ù wš w w. ethanol x ƒ j ƒ k. 5) n z w. w z w z w w yƒ ù. š z x w y j wš. w w naringin flavonoid z w w w š š. t CYP3A4 w dihydropyridine Ca channel blocker wì w z ƒ w š š.( 7) 22) 6) Áyw Áyw p w x w ƒ w» w. t 2ƒ 3ƒ cation k p w w w k. 23,24) w 1) (Protein) š, k y w. w w š, k y z (interdrug), (intersubject) ƒ j. š mixed-function oxidase system(mfos) y w ƒ. 25) Berlinger t (allopurinol) t (oxypurinol) š mw w j p (creatinine clearance) y š. j p (creatinine clearance) y w w x y mw w mw y ƒ. 26)
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