Allopurinol

The bioavailability of drugs is determined by gastrointestinal physiological factors and the physicochemical property of drugs. The presence of food changes the physiological functions of gastrointestinal mucosa (e.g., gastric pH, gastric emptying, hepatic blood flow) which may lead to increase or decrease in the bioavailability of drugs1,2. Intestinal absorption of penicillin, captopril, ciprofloxacin, quinidine and zidovudine was reported to be reduced when given with food. On the other hand, bioavailability of clarithromycin, griseofulvin and leukotriene antagonists was increased by the presence of food. It is difficult to predict the interaction of drug with food based on its chemical structure.

The food habits of different populations vary and the dietary composition was shown to alter the bioavailability of drugs. The dietary intake of carbohydrate, protein, lipids, micronutrients and phytochemicals will change based on the dietetic habits of the population.

Excessive intake of carbohydrate was reported to delay the gastric emptying, raise gastric pH and increase luminal fluid volume which may alter the bioavailability of drugs (e.g., indinavir, phenytoin). Oral glucose treatment decreased the AUC of propranolol. The activities of hepatic CYP1A2, 2C6, 2C11 and 3A2 enzymes were shown to be significantly decreased in glucose treated rats compared to controls3,4.

Dietary proteins affect the function of mixed function oxidase system and conjugating enzymes5·6. Intake of high protein diets was shown to enhance the metabolism of numerous drugs such as cholestyramine, tetracycline. Low intake of protein was reported to cause 20-40 per cent decrease in phenazone and theophylline clearance. The conjugation of acetaminophen and oxazepam was decreased on changing from high protein to low protein diet. It was reported that feeding a charcoal broiled beef diet markedly lowered the plasma concentration of phenacetin without altering the plasma half life suggesting that first-pass phenacetin metabolism is enhanced7. Low protein diet decreased the renal clearance of allopurinol and oxypurinol8.

The ingestion of lipids stimulates the secretion of bile and pancreatic juice. The presence of bile facilitates the dissolution and solubility of low lipid soluble drugs in the intestine. It has been reported that bile increases the dissolution rate of griseofulvin, danazol, etc., that may affect the entry of drugs in the intestine9. Studies have shown that microsomal oxidation is impaired by total parenteral nutrition. This effect may be altered when the caloric source changes from carbohydrate to lipid, especially when administered as medium-chain/long chain triglyceride mixtures10.

In our country, a few studies have been done on diet-drug interaction. Multiple dose administration of Coca cola has been shown to increase the bioavailability of phenytoin and ibuprofen in rabbits11-13. They also reported that high fat diet (butter) increased the bioavailability of phenytoin and carbamazepine in rabbits. But these data need to be confirmed by human studies. The same group showed that single dose administration of grape fruit juice did not alter the phenytoin bioavailability in epileptic patients and healthy volunteers14. Studies done elsewhere15-17 showed that piperine increases the bioavailability of phenytoin, theophylline, propranolol and curcumin in healthy volunteers. The clinical benefits of these findings need to be established.

The effect of honey on drug kinetics has been studied. Multiple doses of honey significantly decreased the plasma levels of diltiazem and carbamazepine (substrates of CYP3A4) in rabbits18,19. In a human study, single dose administration of honey did not alter the carbamazepine kinetics20. In contrast to above, multiple doses of honey significantly increased the rate and extent of absorption of phenytoin (substrate of CYP2C9) in rabbits21. Since, honey is ingested commonly for various purposes by all age groups, a detailed study on its interactions with drugs is warranted.

Recent studies show that CYP3A4 and P-glycoproteins (P-gp) have important role in limiting the bioavailability of drugs22. CYP3A4, one of the important cytochrome P450 enzymes, is found in the columnar epithelial cells lining the intestinal lumen, besides liver and other organs. It metabolises about 50 per cent of the currently available drugs. The activities of CYP3A4 are known to be induced (rifampicin) or inhibited (ketoconazole) by many drugs. It is also sensitive to dietary effects. Grapefruit juice, red wine, green tea and ginseng were reported to inhibit the CYP3A4 activity. Herbal drugs like St.John's wort and Echinacea induced this enzyme23-24. These effects may profoundly affect the oral bioavailability of drugs.

P-glycoprotein is an efflux transporter localized in the apical membrane of the intestinal cells, besides other drug eliminating organs. It actively extrudes drugs from the cell back into the intestinal lumen. CYP3A4 and P-gp. work together to co-ordinate an absorption barrier against xenobiotics. Similar to CYP3A4, P-gp activity can be induced (clotrimazole, erythromycin, phenobarbital, rifampicin) or inhibited (quinidine, verapamil) by drugs 25,26. The influence of diet on the P-gp activity is poorly studied. Flavanoids, particularly flavanols and coumarines were found to modulate P-gp function. In a human study27, administration of grapefruit juice was shown to inhibit P-gp activity leading to increased bio-àvailability of talinolol. In an in vitro study, methoxyflavones (a component of orange juice) specifically inhibited P-gp without altering the CYP3A4 activity28. This may have potential clinical application for reversing the multi-drug resistance of anti-cancer drugs. Other studies have shown that CYP3A4 and P-gp are coregulated through the nuclear receptor like SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor)29. The effects of dietary component on this receptor need to be investigated.

In this issue, Sharma et al30 describes the effects of north Indian and south Indian breakfasts on the bioavailability of lamotrigine. The north Indian diet has high calorie and high fat compared to the south Indian diet. Both types of diets significantly decreased the bioavailability of lamotrigine when compared with the fasting group. Since lamotrigine is having a narrow therapeutic index, this finding may be clinically important. The two types of breakfasts did not produce differential effects on lamotrigine absorption. In contrast, in an earlier study31 the north Indian diet (poori with dal fry) was found to significantly increase the bioavailability of cefuroxime axetil when compared to south Indian diet (idly with chutney). This difference may be due to the difference in physicochemical property and/or pharmacokinetic profile of lamotrigine and cefuroxime axetil.

India is a vast country with populations having different dietary habits. The dietary composition of Indian diet is different from that of the western diet. Jndian diet has more phytochemicals, besides having other differences in the macro-and micronutrietns composition. Therefore, more research is needed to investigate the diet-drug interaction in our population. Since several phytochemicals were shown to modulate the CYP3A4 and P-gp activities, future research should have more focus on this.

References

1. Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 2000; 22 : 131-6.

2. Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet 2003; 42 : 1071-88.

3. Carver PL, Fleisher D, Zhou SY, Kaul D, Kazanjian P, Li C. Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients. Pharm Res 1999; 16 : 718-24.

4. Stewart CC. Strother A. Glucose consumption by rats decreases cytochrome P450 enzyme activity by altering hepatic lipids. Life Sci 1999; 64 : 2163-72.

5. Anderson KE. Influences of diet and nutrition on clinical pharmacokinetics. CHn Pharmacokinet 1988; 14 : 325-46.

6. Walter-Sack I, Klotz U. Influence of diet and nutritional status on drug metabolism. Clin Pharmacokinet 1996; 31 : 47-64.

7. Conney AH, Pantuck EJ, Hsiao KC, Garland WA, Anderson KE, Alvares AP, et al. Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef. Clin Pharmacol Ther 1976;20:633-42.

8. Delzenne NM, Verbeeck RK. Interactions of food and drug metabolism. J Pharm Belg 2001; 56: 33-7.

9. Wade AE. Effects of dietary fat on drug metabolism. J Environ Pathol Toxicol Oncol 1986; 6 : 161-89.

10. Jorquera F, Culebras JM, Gonzalez-Gallego J. Influence of nutrition on liver oxidative metabalism. Nutrition 1996; 12: 442-7.

11. Kondal A, Garg SK. Influence of an acidic beverage (Coca-Co 1 a) on the pharmacokinetics of phenytoin in healthy rabbits. Methods FindExp Clin Pharmacol 2003; 25 : 823-5.

12. Kondal A, Garg SK.Influence of acidic beverage (Coca-Cola) on pharmacokinetics of ibuprofen in healthy rabbits. Indian J Exp Biol 2003; 41 : 1322-4.

13. Sidhu S, Malhotra S, Garg SK. Influence of high fat diet (butter) on pharmacokinetics of phenytoin and carbamazepine. Methods Find Exp Clin Pharmacol 2004; 26: 634-8.

14. Kumar N, Garg SK, Prabhakar S. Lack of pharmacokinetic interaction between grapefruit juice and phenytoin in healthy male volunteers and epileptic patients. Methods Find Exp Clin Pharmacol 1999; 21 : 629-32.

15. Velpandian T, Jasuja R, Bhardwaj RK, Jaiswal J, Gupta SK. Piperine in food: interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet 2001; 20:241-7.

16. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-6.

17. Bano G. Raina RK, Zutshi U, Bedi KE, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol 1991; 41 : 615-7.

18. Koumaravelou K, Adithan C, Shashindran CH, Asad M, Abraham BK. Influence of honey on orally and intravenously administered diltiazem kinetics in rabbits. Indian J Exp Biol 2002; 40 : 1164-8. Erratum in: Indian JExp Biol 2002; 40: 1328.

19. Koumaravelou K, Adithan C, Shashindran CH, Asad M, Abraham BK. Effect of honey on carbamazepine kinetics in rabbits.Indian J Exp Biol 2002; 40 : 560-3.

20. Malhotra S, Garg SK, Dixit RK. Effect of concomitantly administered honey on the pharmacokinetics of carbamazepine in healthy volunteers. Methods Find Exp Clin Pharmacol 2003; 25 : 537-40.

21. Sukriti, Garg SK. Influence of honey on the pharmacokinetics of phenytoin in healthy rabbits. Methods Find Exp Clin Pharmacol 2003; 25 : 367-70.

22. Fujita K. Food-drug interactions via human cytochrome P450 3A (CYP3A). Drug Metabol Drug Interact 2004; 20: 195-217.

23. Moore LB, Goodwin B, Jones SA, wisely GB, SerabjitSingh CJ, Willson TM, et al. St. John's wort induces hepatic drug metabolism through activation of pregnane X receptor. ProcNatlAcadSci USA 2000; 97:7500-2.

24. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, et al. The effect of Echinacea (Echinacea purpurea root) on cytochrome P 450 activity in vivo. Clin Pharmacol Ther 2004; 75: 89-100.

25. Sun J, He ZG, Cheng G, Wang SJ, Hao XH, Zou MJ. Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. Med Sd Monit 2004; 10: RA5-14.

26. Deferme S, Augustijns P. The effect of food components on the absorption of P-gp substrates: a review. J Pharm Pharmacol 2003; JJ : 153-62.

27. Lo YL, Huang JD: Comparison of effects of natural or artificial rodent diet on etoposide absorption in rats. In Vivo, 1999; 13:51-5.

28. Takanaga H, Ohnishi A, Yamada S, Matsuo H, Morimoto S, Shoyama Y, et al. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. JPharmacol Exp Ther 2000; 293: 230-6

29. Synold TW, Dussault I, and Forman BM: The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med2001 ; 7:584-90.

30. Sharma C, Dubey R, Kumar H, Saha N. Food reduced the bioavailability of lamotrigine. Indian J Med Res 2005; 121 : 658-63.

31. Vasu S, Adithan C, Shashindran CH, Asad M, Koumaravelou K, Topno I. Effect of two types of Indian breakfast on bioavailability of cefuroxime axetil. Indian J Med Res 2000; 112: 104-8.

C. Adithan

Department of Pharmacology

Jawaharlal Institute of Postgraduate Medical

Education & Research, Pondicherry 605006, India

e-mail: jipgene@jipmer.edu

Copyright Indian Council of Medical Research May 2005
Provided by ProQuest Information and Learning Company. All rights Reserved