Drug Absorption and Intestinal Components Essay

Introduction

Drug absorption is defined as the movement of a drug into the bloodstream (Birckelbraw, 2007). Among the factors that can affect the absorption process are the ways the drug is designed and manufactured, its physical and chemical properties and the physiological characteristics of the person taking the drug. A drug product can be explained as the actual dosage form of a drug, which consists of two ingredients which are the drug (active ingredient) and the additives (inactive ingredients) (Kopacek, 2007).

The blood level of the drug may become too high if a tablet releases the drug too quickly, thus, causing an excessive response. Contrastingly, if the tablet releases the drug at a much slower pace, most of the drug may be eliminated without being absorbed, which may result in blood levels being too low.

Drug manufacturers create the tablet to release the drug at the desired speed. Thus, drug products that contain the same drug may have different inactive ingredients, which also cause the absorption of the drug from different products to vary. Drug products that not only contain the same active ingredient but also produce virtually the same blood levels at the same points in time are considered bioequivalent. Bioavailability is affected by food, other drugs, and digestive disorders (Hauss, 2007).

For instance, high-fibre foods may bind with a drug which may prevent it from being absorbed. Drug absorption may be reduced as Laxatives and diarrhoea, which speed up the passage of substances through the digestive tract. Apart from that, surgical removal of parts such as the stomach or colon may also affect drug absorption. Besides that, where and how long a drug product is stored can affect drug bioavailability.

The process of drug absorption is quite complex, and the extent of absorption changes according to the characteristics of the drug. Some of these factors include formulation, solubility and permeability. Intestinal motility, regional permeability differences, pH value, luminal and mucosal enzymes are some of the physiological variables affecting drug absorption. Recent advances in pharmaceutical sciences have led to the development of several quantitative and qualitative methods to determine the extent of oral drug absorption.

Noyes Whitney equation relates the rate at which a drug dissolves to the properties of the solid and the dissolution medium. This equation is based on the diffusion layer model of dissolution and uses a quantitative analysis that relates the amount of time taken to dissolve a drug from solid particles. It governs the rate at which drugs are absorbed by the intestinal membrane and is very critical in pharmaceutical science. It explains how solubility and surface area can affect dissolution rate.

dC/dt = (D. A)/h (C_s – C)

• C is the drug concentration in the solvent.
• Cs is the drug concentration in solvent in the diffusion layer
• dC/dt is the rate at which a drug dissolves
• A is the surface area of the solid
• D is the dissolution rate constant
• h is the thickness of the diffusion layer

It is important that a drug’s solubility in lipid, as well as aqueous liquids, be considered. Any effective drug should some soluble in both lipid and aqueous solutions to a reasonable degree. This is because lipid solubility is needed for a drug to cross biological membranes.

Any drug also needs to have aqueous solubility to ensure its distribution into the systemic circulation and other bodily fluids. Although solubility is constant at a given temperature and pressure, the rate at which the drug dissolves can vary depending on the particle size of the solute and the agitation rate of the solution. Certain drugs that are not quite soluble in water may exhibit poor absorption characteristics, such as erratic or incomplete absorption. However, this can be prevented by modifying the drug’s aqueous solubility. This can be accomplished by the following methods,

• Adjusting pH of a liquid formulation.
• Structural modification of the drug.
• Adding co-solvents to improve solubility.

The time needed for a drug to dissolve in intestinal liquids is known as the dissolution rate. It controls the bioavailability of the drug by means of dosage since dissolution rate is a rate-limiting step during absorption. The dosage levels of all solid drug forms such as tablets, capsules and intramuscular suspensions depend upon the drug’s dissolution rate and thereby improve bioavailability. Some of the methods to improve dissolution rates are as follows,

• Using the ionized form of the drug can help increase solubility in the diffusion layer. For instance, using penicillin V potassium instead of penicillin V will make the drug dissolve faster and have a faster effect on the patient’s health.
• Decreasing the particle size of the drug would, in turn, increase the surface area available for dissolving fluid.
• The dissolution medium’s agitation can be increased to improve the dissolution rate. This technique is commonly used in effervescent, buffered aspirin.
• The pH values of the dissolution medium can also be changed to bring out an increase in the dissolution rate of a drug.

Drug dissolution modelling, absorption models based on structure and dynamic systems for oral absorption are approaches being developed by researchers to understand better the factors affecting oral drug absorption. The biopharmaceutic classification of drugs and regulatory aspects of oral drug absorption are some aspects that are constantly debated in pharmaceutical circles. Vitro data collected provides models for the dissolution and release of the drug. The results obtained from these models are quite reasonable. These vitro-in vivo correlations are complied official using special computer packages.

Review and Discussions

Some researchers have recently been able to develop a segregated flow model consisting of a separate intestinal tissue to both the outermost absorptive layer and non-absorptive layer, on the basis of conducting a physiological study(Dresser,2006). This was done to describe the absorption of route-dependent morphine glucuronidation in the small intestine, which was superior compared to conventional physiologically-based models.

These models were further enhanced from mere theoretical simulations to segmental segregated flow model and traditional segmental model. This was done in order to observe the intestine as three separate parts of the same lengths. Each of these segments got equal flows to ensure that the segmental transporter and metabolic functions are heterogeneous. The heterogeneous nature of absorption, metabolism and exsorptive functions affect factors like bioavailability, drug clearance and metabolite formation.

Intravenous and oral dosing in the intestine was studied when the tissue is the removal organ. Simulations were conducted for different gastrointestinal transit times, under various conditions like the drug partitioned readily by flow-limited distribution and the drug flowing slowly into intestinal tissue by membrane-limited distribution (Rommer, 2005). It was discovered that clearance in the intestine was reciprocally correlated to the absorption rate constant of drugs subjected to secretion.

It was also directly related to the secretory and metabolic clearances. Bioavailability was reciprocally related to the metabolic and secretory clearances while being directly related to the rate of absorption constant. Metabolite formation and bioavailability were reduced as a result of gastrointestinal transit time. However, gastrointestinal transit time played a role in increasing the level of clearance. Bioavailability decreased with a reduction in intrinsic metabolic clearance, while bioavailability had a higher value when the segmental distribution of intrinsic metabolic clearance was increased.

Another group of researchers have concluded that synthetic and natural surfactants are used in a drug formulation; its possible effect on drug absorption must be measured. Apart from that, a pharmacological agent must reach its target to exert a therapeutic effect as, therefore, factors that influence absorption has little effect on their pharmacokinetics. Also, oral delivery necessitates careful consideration of the various factors that influence drug absorption because interactions with other orally directed substances such as food can change bioavailability.

However, there has been increasing interest in the oral delivery of anticancer agents in chronic therapy for patient convenience and ease of administration. Food-drug interactions can have four pharmacokinetic effects on the bioavailability, which are delayed, decreased, increased or unaffected absorption.

An experiment concluded that delayed absorption slowed the rate of gastric emptying. A prolonged time in the stomach results in an increased rate of hydrolysis and decreases bioavailability. Some orally administered anticancer such as capecitabine, altretamine, etoposide phosphate and estramustine phosphate sodium agents are pro-drugs that require activation (Svein, 2006). By scheduling the oral administration of anticancer agents with reference to meal timing either before, during or after a meal, food-drug interactions are optimally managed to improve chemotherapy outcomes. Therefore, factors that alter the absorption of these medications can have profound effects on their pharmacokinetics.

Contrastingly, food has been shown to have only a minor effect on pharmacokinetics, and the rate of absorption is decreased in a fed state, which results in an increase in hepatic first-pass metabolism, which in turn reduces the extent of systemic absorption of the pro-drug. The absorption of orally administered anticancer agents that are not pro-drugs can also be altered by metabolism within the gastrointestinal tract. It has been known for years that the optimum dose required for many therapeutic agents among individuals is quite variable; however, like many of the studies reported in the literature, the reason for such variability is unknown.

Conclusion

Perhaps one of the most challenging areas in pharmacology research in our 21st century is to understand to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions and why individuals respond differently to drug therapy, and the effects of bioavailability. In order to answer the above questions, research has been done, and drug-metabolism research will depend on various different approaches more than ever to investigate the various components involved in drug metabolism and disposition(Persson, 2005).

Among some of the major research challenges are taken from referencing various research papers and are such as the genetic variation of drug targets, for example, receptors and enzymes; drug transporters like multispecific organic anion transporter and drug-metabolizing enzymes; the mechanism of idiosyncratic adverse drug reactions; the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; the induction, repression, and inhibition of all components involved in drug disposition; and the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety.

For the future, in order for successful drug-metabolism research to be conducted, especially in the new millennium, research must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety(Rommer, 2005).

Recommendations/Further work

Most pharmaceuticals, as well as hospitals and also some medical companies, are devoting their efforts to establishing the involvement of a specific gene or a group of genes in certain diseases, while others are genotyping patients in clinical trials(Dressman, 1998).

This drug absorption research is also being carried out on most patients in order for the doctors and pharmacists to try to come up with one drug for all patients. Thus, with a better understanding of gene variations and the effect of such variations on pharmacodynamics and pharmacokinetics, it is hoped that maximum drug response can be achieved in drug therapy by compensating for individual variability.

Drug bioavailability is lowered by the inhibition of intestinal uptake transporters due to fruit juices. Recent findings of fruit juices interaction with drug absorption continue to enhance our understanding of the complex nature of food–drug interactions and their possible influence on the clinical effects of medications. Presently, there are many researchers in this field that are studying drug interactions with certain foods to identify how a drug’s efficacy is affected by this. To accomplish this, we have to clearly elucidate the role of P-gp and OATP during the interaction of food with drugs (Anthony,1998).

In addition, more studies are needed to clarify interactions involving OTC medications and herbal medications. For instance, dose-dependent CYP inhibition has been observed following administration with grapefruit juice, but changes in pharmacokinetics, which could result in toxic drug exposure, are difficult to predict as the mechanism seems to be multifactorial. Therefore, clinical trials that evaluate orally administered anticancer agents typically prohibit the use of certain foods and juices(Dresser,2006). P-glycoprotein is located on the apical membrane of intestinal epithelial cells. Intestinal absorption is limited and therefore decreases the bioavailability of orally administered agents since P-glycoprotein is orientated in such a way that substrates are secreted from the epithelial cell back into the intestinal lumen.

In addition to being substrates for this transporter, some medications, as well as food and herbal products, can inhibit its activity, which leads to interactions with other drugs(Miller, 2002). However, academics and scientists are testing for more fruits and their contents to try and find more solutions, especially to create a better drug absorption outcome. Realizing that the current “one-medicine-fits-all” approach can not satisfactorily treat all patients as everyone has different reactions to a drug thru their drug absorption issue, academic and industrial scientists are gradually directing their research activities toward the goal of achieving individualized medicine whereby they try to create a specific drug for a certain group of people.

Pharmacogenomics, which relates genomic function to molecular pharmacology, promises to redefine basic notions in drug discovery and disease management. Pharmacogenomics is still a relatively new area that is being researched, according to several articles. From the above research done, we can conclude that drug absorption has been studied over a long period of time to enable more positive outcomes for its patients(Fricker, 2002).

However, along with positive outcomes, there were also some negative ones found. Thus, the research process doesn’t stop as we keep on discovering newer discoveries and newer downsides and so on. Thus, it is important for the research process to be carried on continuously even in future, as we can never stop learning from what we know as every day there can be a new discovery.

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