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1 w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No 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: , Fax: 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

2 148 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 ¾ 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

3 y w w 149 w t ph 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

4 150 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

5 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)

6 152 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)

7 y w w 153 2) k y (Carbohydrate) k y e w w w. w 27) Kappas š šk y w pv (antipyrine) l v (theopylline) y w š. k 25) y y (oxidation) mw ùkü w, MFOS y w. 3) (Lipid) s w wù. s w y ùkü. MFOS y û. 28) š š w x ƒ ƒ x x w wš w ww. w x ƒ ùký. w w w ù. wù œ (triglyceride) wƒ ƒw x ƒ ƒw w ww. 29) 4) k (Vitamins) (niacin) v (riboflavin) k B MFOS w y w. k A, E, C s w v w k cytochrome P450 w ww š MFOS y ww y û ) k w w ùkú. dw e w» w q(levodopa) n wš y v (pyridoxine) y yw z ƒ ùkù. š 33) (folic acid) mp p(methotrexate) z k. š k Kƒ g t q (warfarine) w šz k. 34) y e z j ù w ùký. w n y w y w. w y mw ƒ w w. š w š, w w. ù ù y w. w - y w w. ƒ w ƒ z n mw - y wš w. w wì w š w y ù z ùký. w 35) w w y ü y w»» mw. w mw ƒ y w w. š x 1. M. Gibladi, Biopharmaceutics and clinical pharmacokinetics 3 rd edition, Lea & Febiger, Malvern, Pa, p Remingtons s Pharmaceutical Science 17 th edition, Mack Publishing Co., Easton, Pa, p Y. Kwon, Handbook of essential pharmacokinetics, pharmacodynamics and drug metabolism for industrial scientists, Plenum Publishers, New York, p H.C. Ansel, N.G. Popovich, Dosage form design: Biopharmaceutic consideration, Pharmacutical Dosage Form and Drug Delivery Systems, 5th edition. Lea & Febiger, Malvern, P, pp , (1990) 5. R.D. Toothaker, P.G. Welling. The effect of food on drug bioavailability. Ann Rev Pharmacol Toxicol. 1980; 20: ) M. Gibaldi D. Perrier, Pharmacokinetics 2nd edition, Marcel Dekker, New York, N.Y, p t,,, p B.B. Brodie, C.A. Hogben, Some physio-chemical factors in drug action, J. Pharm. Pharmacol., 1957; 9(6): w,,, p M. Rowland, T.N.Tozer, Clinical pharmacokinetics Concept and Application, Lea & Febiger, Melvern, Pa., p , 11. D.Winne, J.Remischovsky, Intestinal blood flow and absorption of non dissociable substance, J.Pharm.Pharma-

8 154 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 col., 1970; 22: I.R.Rowland. Drug Metabolism Reviews, Marcel Dekker, New York N.Y., p , 13. R.S. Goldstein, J.P.Chism, J.M.Sherril et al. Influence of dietary pectin on intestinal microfloral metabolism and toxicity of nitrobenzene. Toxicol. Appl. Pharmacol., 1984;75: P.G.Welling. Pharmacokinetic Basis for Drug Treatment, Raven Press, New York, N.Y., p , 15. D.B. Williams, W.J O'Reilly, G.Boehm et al. Absorption of doxycycline from a controlled release pellet formulation: The influence of food on bioavailability. Biopharm. Drug Dispos., 1990;11: M.A.Osman, R.B.Patel, A.Schuna et al. Reduction in oral penicillamine absorption by food, antacid, and ferrous sulfate. Clin. Pharmacol. Ther. 1983; 33: P.G Welling, H.Huang, P.F.Hewitt et al. Biovailability of erythromycin stearate: Influence of food and fluid volumn. J.Pharm.Sci., 1978; 67: G.. Dongowski, B. Fritzsh, J. Giessler et al. The influence of bile salts and mixed micelles on the pharmacokinetics of quinine in rabbits. Eur. J. Pharm. Biopharm., 2005; 60: R.G.Crounse, Human pharmacology of griseofulvin: the effect of fat intake on gastrointestinal absorption, J. Invest. Dermatol., 1961; 37: H.Y. Yun, J.H. Kim, E.J. Lee, S.Y. et al. Effect of food on pharmacokinetics and pharmcodynamics of fenofibric acid after a single oral dose of fenofibrate sustrainedrelease capsule, Kor. J. Clin. Pharm., 2005; 15: H.Y. Yun, E.J. Lee, S.Y. Chung, S.O. Choi, H.K. Kim, J.T. Kwon, W.K. Kang, and K.I. Kwon, The effects of food on the bioavailability of fenofibrate administered orally via sustained-release capsules in humans, Pharmacokinet., 2006;45(4): Clin. 22. K.S. Lown, D.G. Bailey, R.J. Fontana, S.K. Janardan, C.H. Adair, L.A. Frontlage, M.B. Brown, W. Guo, and P.B. Watkins, Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression, J. Clin. Invest., 1997; 99(10): J.A. Cambria-Kiely. Effect of soy milk on warfarin efficacy. Ann Pharmacother., 2002;36: T.O. Dheng. Potential interaction between soy milk and warfarin. Am Fam Phys., 2004;70: K.E. Anderson, A.H Conney, A. Kappas. Nutrition and oxidative drug metabolism in man: Relative influence of dietary lipids, carbohydrate, and protein. Clin Pharmacol Ther. 1979;26: A. Kappas, K.E. Anderson, A.H Conney. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man, Clin Pharmacol Ther. 1976;20: W.G. Berlinger, G.D. Park, R. Spector. The effect of dietary protein on the clearance of allopurinol and oxypurinol. N Engl J Med. 1985; 313: K.E Anderson, E.J. Pantuck, A.H. Conney. Nutrient regulation of chemical metabolism in humans. Federation Proc. 1985; 44: P. Welling. Nutrient effects on drug metabolism and action in the elderly. Drug Nutrient Interactions. 1985; 4: F.P. Guengerich. Effects of nutritive factors on metabolic processes involving bioactivation and detoxification of chemicals. Ann Rev Nutr. 1984; 4: J.N. Hathcock. Metabolic mechanisms of drug-nutrient interactions. Federation Proc. 1985; 44(I): R.G. Thurman, F.C. Kauffman. Factors relating drug metabolism in intact hepatocytes. Pharmacol Rev. 1980; 31: G.C. Cotzias. Metabolic modification of some neurologic disorders. JAMA. 1969; 210: K.E. Anderson. Influences of diet and nutrition on clinical pharmacokinetics. Clin Pharmacokinet. 1982; 32: F.M. Shannon, S. Micheal. Drug interaction-a review. Cllin Pediatr., 2005; 6(2):

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15(1)-04(국)(p.27-33).fm w wz «y Kor. J. Clin. Pharm., Vol., No.. y sƒ Áwx Á ³ Á Ÿ y w w w w w Analysis of Drug Use Reviews in Pediatirc Inpatients Eun Jeong Shin, Hun Joo Ha Wan Gyoon Shin and Kwang Jun Park Graduate School of