Food-drug Interaction Studies Research Articles

Design and statistics of pharmacokinetic drug-drug, herb-drug, and food-drug interaction studies in oncology patients

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.

Pharmacokinetics of trazodone sustained-release tablets in healthy subjects: Three open-label, randomized crossover studies .

To characterize the pharmacokinetics of trazodone hydrochloride (HCl) sustained-release tablets (TSR) and trazodone immediate-release formulation (TIR) and investigate the effects of food on the pharmacokinetics of the drug in healthy subjects. Three open-label, randomized crossover trials of single-dose, multiple-dose, and food-drug interaction testing were conducted. A validated high-performance liquid chromatography-fluorescence method was used to measure the plasma concentration of trazodone, and a non-compartment model was used to obtain the pharmacokinetic parameters. AUC and Cmax dose proportionality were analyzed using a power model. TSR lacked dose proportionality over a dose range of 25 - 150 mg. In the food-drug interaction study, no significant changes in the pharmacokinetic parameters of the drug under the fed conditions were observed. Multiple dosage of TSR and TIR reached steady state after 7 days, with no accumulation phenomenon observed. The peak time and peak concentrations of TSR were significantly longer and lower, respectively, than those of TIR. TSR showed clear sustained-release characteristics, and food exhibited no significant effects on the pharmacokinetic parameters of trazodone. TSR and TIR reached steady state levels after 7 consecutive days of administration, with no accumulation phenomenon observed.

Effect of purple grape juice on the pharmacokinetics of digoxin: Results of a food-drug interaction study

Digoxin is a glycosidic, cardiotonic plant extract with a narrow therapeutic window. The purpose of the study was to investigate the effects of purple grape juice on the pharmacokinetics of digoxin in rats. A randomized, controlled, single- and multiple-dose study was conducted to evaluate the pharmacokinetic profiles of orally and intravenously administered digoxin. The plasma concentration of digoxin was determined by radioimmunoassay using a gamma counter, and a Caco-2 cell transport model was used to investigate the potential mechanism by which purple grape juice affects the pharmacokinetics of digoxin. The results show that multiple-dose purple grape juice caused a remarkable increase in the AUC, Cmax, and Ka of orally administered digoxin (p < 0.05); only a single dose increased the digoxin AUC0-∞ by 72.80% (p < 0.05). Other parameters were not significantly affected. The study of intravenously administered digoxin found no significant difference in the pharmacokinetic characteristics of the two dosing groups (p > 0.05). The Caco-2 transwell experiments indicated that both the pure purple grape juice and its ethyl acetate extract significantly inhibited digoxin basolateral-to-apical (B→A) transport at concentrations of 10%, 30%, and 50% with dose dependency. These results confirmed that the improvement in bioavailability of digoxin resulted from the inhibition of P-gp by purple grape juice at the level of the gastrointestinal wall. Purple grape juice can increase the bioavailability of orally administered digoxin, especially with multiple doses. This information suggests that co-administration of oral digoxin and purple grape juice may require a dose adjustment. .

Food Effect on Oral Bioavailability: Old and New Questions.

Food Effect on Oral Bioavailability: Old and New Questions.

A Review-Drug-Food Interactions

Although it is well known and identified that drug-drug interactions exist, the recognition of importance of food and drug interactions to practice has been growing much slower. On the other hand, drug-food/nutrient interactions continue to grow with the common use of medications. Beside the awareness of this type of interactions, food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. Drug-food interactions take place mechanistically due to altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion. In addition, some people have greater risk of food and drug interactions that have a poor diet, have serious health problems, children's and pregnant women. In this article, basic information's about importance, classifications, transporters and enzymes of drug and nutrient interaction are given and some specific examples of both drug and nutrients and influences on each other are included.

Influence of Food on Paediatric Gastrointestinal Drug Absorption Following Oral Administration: A Review.

The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations.

FÁRMACOS E ALIMENTOS: INTERAÇÕES E INFLUÊNCIAS NA TERAPÊUTICA

Interações entre fármacos e alimentos podem ser determinantes na obtenção do sucesso terapêutico, devido a interferências tanto no metabolismo de fármacos quanto na absorção de nutrientes. O objetivo deste trabalho foi realizar uma revisão bibliográfica sobre interações fármaco-alimento de impacto à saúde, bem como discutir as medidas adequadas para evitá-las ou minimizá-las. A literatura indica que as interações fármaco-alimento mais importantes são aquelas que afetam a biodisponibilidade do fármaco, sendo que muitas delas possuem mecanismos completamente elucidados. Estes estudos são importantes contribuições para o uso correto de medicamentos e possibilitam a elaboração de protocolos clínicos adequados.

Food and Drug Interactions: A General Review

Although it is well known and identified that drug-drug interactions exist, the recognition of importance of food and drug interactions to practice has been growing much slower. On the other hand, drug-food/nutrient interactions continue to grow with the common use of medications. Beside the awareness of this type of interactions, food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. Drug-food interactions take place mechanistically due to altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion. In addition, some people have greater risk of food and drug interactions who have a poor diet, have serious health problems, childrens and pregnant women. In this article, basic informations about importance, classifications, transporters and enzymes of drug and nutrient interaction are given and some specific examples of both drug and nutrients and influences on each other are included.

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

Development and validation of a gradient elution high-performance liquid chromatographic method for determination of talinolol in rat plasma: Application to a preclinical food-drug interaction study

A sensitive and reproducible high-performance liquid chromatographic (HPLC) method for determination of talinolol (TAL) in rat plasma was developed and validated using pindolol (PIN) as an internal standard. Both TAL and PIN were separated on a Zorbax Eclipse XDB C18 column by gradient elution with 0.1% aqueous formic acid and acetonitrile as the mobile phase. Detection was performed using fluorescence measurement at λex 249 nm and λem 333 nm. The method was validated and found to be linear in the range of 10–2000 ng mL−1. The limit of quantification was 10 ng mL−1 based on 100 μL of plasma. The variations for intra- and inter-day precision were less than 10%, and the accuracy values were between 92% and 102.9%. The extraction recoveries were more than 82%. The assay was successfully applied to an in-vivo pharmacokinetic study of TAL in rats that were administered a single oral dose of 10 mg kg−1 TAL. The maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC0–12) were 0.369 ± 0.024 μg mL−1 and 1.429 ± 0.027 μg h mL−1, respectively. The modulatory effect of apricot juice on P-glycoprotein-related efflux carriers was also investigated. Co-administration of apricot juice resulted in a significant increase of the amount of TAL in plasma (Cmax and AUC0–12 were 0.679 ± 0.021 and 2.357 ± 0.079, respectively; p < 0.05).

In vitro food–drug interaction study: Which milk component has a decreasing effect on the bioavailability of ciprofloxacin?

The purpose of the present work was developing an in vitro dissolution test to highlight the possible molecular background causing ciprofloxacin (CPFX)–milk interaction. The in vitro dissolution of CPFX from film-coated tablets (Ciprinol ® 500 mg) was examined at different pH values, simulating certain parts of the gastrointestinal tract, in the presence of water, low-fat milk, casein- or calcium enriched water. In order to determine the amount of dissolved CPFX, solid phase extraction sample preparation followed by high performance liquid chromatography coupled with mass spectrometry was applied. Comparing the dissolution efficiency values in various media, it can be concluded, that casein has a more pronounced effect on the absorbable amount of the antibiotic at each pH value studied, than calcium. In the case of concomitant intake of CPFX film-coated tablet and milk or other dairy products not only the complexation with calcium, but also the adsorption of CPFX on the surface of proteins decreases the absorbable amount of CPFX.

In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice

Grapefruit juice is responsible for many drug interactions but the exact components involved in this interaction are not precisely known. Flavonoids and furocoumarin derivatives such as naringenin and bergamottin, respectively, could be involved in the inhibition of drug metabolism. The objective of this paper is to investigate in vitro the possible metabolic hepatic interaction between simvastatin (SV) and bergamottin (BG) and thus to compare its effects to those of naringenin (NRG) the aglycone form of naringin (NR) (a flavonoid present in grapefruit juice). In human and rat microsomes and in rat hepatocytes, BG was found to be a mixed type inhibitor of SV metabolism. In rat liver microsomes the K i value of BG ( K i=174±36 μM) is higher than the K i value of NRG ( K i=29±11 μM). However, in human liver microsomes the K i values are similar in BG and NRG ( K i=34±5 μM and 29±11 μM, respectively). Moreover, it seems that there is an interspecies difference between human and rat hepatic metabolism of SV involving different isoenzymes of CYP 450. In conclusion, our study shows that BG inhibits SV metabolism. BG and NRG could therefore be applied as markers in food–drug interaction studies in order to adjust posology.

On the assessment of effects of food on the pharmacokinetics of drugs in early development.

The impact of food on the pharmacokinetics of a drug has important implications in drug development. This commentary is aimed at addressing two key challenges, developability of drugs whose pharmacokinetics are severely influenced by food, and the need for addressing the effects of fruit juice ingredients which modulate metabolic/efflux properties of a compound. Perspectives on the value in predicting food-drug interactions during preclinical development, timing of clinical food-drug interaction studies, and implications of food effects are presented herein.

Is It Really OK to Take This with Food? Old Interactions with a New Twist

In response to consumers' increased interest in preventive health care, the food industry is producing a variety of foods fortified with calcium, iron, and other minerals and vitamins. This well-meaning idea of food fortification is troubling in the context of clinical pharmacology. The recommended Food and Drug Administration (FDA) meal used in food-drug interaction studies is a high-fat, high-calorie meal with little nutritive value. While some drugs may appear to be safe when taken with food, this may not be true when fortified foods are considered. The mechanisms causing drug-fortified food interactions are the same well-known mechanisms that cause other drug-mineral interactions. Certain drugs may exhibit decreased absorption due to chelation and adsorption. Other drugs may have decreased absorption or increased excretion due to changes in gastric and/or urinary pH. The results of such interactions may be clinically insignificant or severe, including treatment failure, frequent dose changes, antibiotic resistance, and increased morbidity and mortality. Revisions of current regulatory guidelines are necessary to take into account this potentially major source of “new” drug interactions.

Is It Really OK to Take This with Food? Old Interactions with a New Twist

In response to consumers' increased interest in preventive health care, the food industry is producing a variety of foods fortified with calcium, iron, and other minerals and vitamins. This well-meaning idea of food fortification is troubling in the context of clinical pharmacology. The recommended Food and Drug Administration (FDA) meal used in food-drug interaction studies is a high-fat, high-calorie meal with little nutritive value. While some drugs may appear to be safe when taken with food, this may not be true when fortified foods are considered. The mechanisms causing drug-fortified food interactions are the some well-known mechanisms that cause other drug-mineral interactions. Certain drugs may exhibit decreased absorption due to chelation and adsorption. Other drugs may have decreased absorption or increased excretion due to changes in gastric and/or urinary pH. The results of such interactions may be clinically insignificant or severe, including treatment failure, frequent dose changes, antibiotic resistance, and increased morbidity and mortality. Revisions of current regulatoryguidelines are necessary to take into account this potentially major source of "new" drug interactions.