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Overview of factors affecting oral drug absorption
Article · September 2004
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Asian Journal of Drug Metabolism and Pharmacokinetics Paper ID 1608-2281-(2004)-0403-00167-10
Copyright by Hong Kong Medical Publisher Received May 29, 2004
ISSN 1608-2281 2004; 4(3): 167-176 Accepted August 10 , 2004
Overview of factors affecting oral drug absorption
Nai-Ning Songa,b, Shao-Yu Zhangb, Chang-Xiao Liua
aTianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China
bDepartment of Pharmacology, College of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Abstract This article provides an overview of variables that can affect drug absorption following oral administration in recent years, including both physicochemical properties of the drug and physiological factors of the body. The oral absorption of a drug is a complex process depending upon these factors and their interactions with each other. Solubility and permeability are considered as the major physicochemical factor that affect the rate and extent of oral drug absorption, moreover other physicochemical properties always show their effects to drug absorption via affecting solubility and permeability. In this regard, the Biopharmaceutics Classification System is proved to be a successful predictive tool for drug development.
Oral drug bioavailability can also be markedly influenced by physiological factors, such as gastrointestinal pH, gastric emptying, small intestinal transit time, bile salt, absorption mechanism and so on. Thus by understanding the physicochemical properties of a compound and by recognizing the physiological processe affecting drug absorption, also with the awareness of a drug’s BCS characteristics, pharmaceutical scientists can better predict drug absorption and develop formulations that can maximize drug bioavailability.
Key words oral drug absorption; bioavailability; the Biopharmaceutics Classification; physicochemical properties;
physiological factors
Introduction
The oral absorption process of drug from a pharmaceutical dosage form is very complex.
However, the major steps occurring during oral drug absorption can be regarded as part of a serial process (Fig.1): (1) The dissolution of the drug from the dosage form；(2) The solubility of drug as a function of its physicochemical characteristics；(3) The drug’s effective permeability to the intestinal mucosa；and (4) The drug’s presystemic metabolism. [1]
______
*This work was a part of National 863 plan No.2003AA2Z374D Correspondence to Prof Chang-Xiao Liu, Tianjin national Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, 308 Anshan West Road, Tianjin, 300193, China
Tel: +86-22-23006863; Fax: +86-22-23006860 E-mail: [email protected]
There are many factors that may affect the above processes, and finally affect the rate and extent of oral drug absorption. These factors can be divided into three categories.[2,3] The first category represents physicochemical properties of a drug, including solubility, intestinal permeability, pKa, lipophilicity, stability, surface area, particle size and so on. The second category comprises physiological factors, such as gastrointestinal pH, gastric emptying, small intestinal transit time, bile salt, absorption mechanism and so on. The third category contains dosage form factors, such as solution, capsule, tablet, suspension and so on.
The purpose of this article is to discuss factors affecting oral drug absorption, including physicochemical properties of the drug, physiological factors of the body, and some effects of formulation.
Also the Biopharmaceutics Classification System (BCS) is introduced in the article as a predictive tool
for identifying compounds whose oral absorption may be sensitive to physicochemical and
physiological variables.
Fig 1. Oral absorption of drugs from a pharmaceutical drug product
The Biopharmaceutical Classification System
The Biopharmaceutics classification system (BCS) has been one of the most significant prognostic tools created to promote product development in recent years.[4] It is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability characteristics, which will substantially facilitate drug product selection and approval process for a large group of drug candidates. The goal of the BCS is to function as a tool for developing in vitro dissolution specifications for drug products that are predictive of their in vivo performance.[5]
According to the BCS, drug substances are classified as follows:
Class 1: High Solubility-High Permeability:
generally very well-absorbed compounds
Class 2: Low Solubility-High Permeability:
exhibit dissolution rate-limited absorption
Class 3: High Solubility-Low Permeability:
exhibit permeability rate-limited absorption
Class 4: Low Solubility-Low Permeability: very poor oral bioavailability.
The Class Boundaries:
A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in≤250 ml water over a pH range of 1 to 7.5.
A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be ≥ 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
A drug product is considered to be
RAPIDLY DISSOLVING when ≥85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of
≤900 ml buffer solutions.
The pH-solubility profile of the test drug substance should be determined in aqueous media with a pH in the range of 1-7.5 using traditional shake-flask method as well as acid or base titration methods. A sufficient number of pH conditions should be evaluated to accurately define the pH-solubility profile. Concentration of the drug substance in selected buffers (or pH conditions) should be determined using a validated stability-indicating assay that can distinguish the drug substance from its degradation products.
The permeability class of a drug substance can be determined in human subjects using mass balance, absolute BA, or intestinal perfusion approaches: 1.
Pharmacokinetic Studies in Humans: a. Mass Balance Studies b. Absolute Bioavailability Studies; 2.
Intestinal Permeability Methods: The following methods can be used to determine the permeability of a drug substance from the gastrointestinal tract: (1) in vivo intestinal perfusion studies in humans; (2) in vivo or in situ intestinal perfusion studies using suitable animal models; (3) in vitro permeation studies using excised human or animal intestinal tissues; or (4) in vitro permeation studies across a monolayer of cultured epithelial cells; 3. Instability in the Gastrointestinal Tract: determining the extent of absorption in humans based on mass balance studies using total radioactivity in urine does not take into consideration the extent of degradation of a drug in the gastrointestinal fluid prior to intestinal membrane
permeation.
Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 mL of the following dissolution media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.
For capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. Two dissolution profiles are considered similar when the f2 value is
≥50.
By understanding the relationship between a drug’s absorption, solubility, and dissolution characteristics, it is possible to define situations when in vitro dissolution data can provide a surrogate for in vivo bioequivalence assessments,that is to find under which circumstances dissolution testing can be prognostic for in vivo performance.[6]
For immediate release formulations of Class 1 drugs, in dissolution tests, the only need is to verify that the drug is indeed rapidly released from the dosage form under mild aqueous conditions.
For Class 2 drugs, in order to establish a strong correlation between the results of dissolution tests and the in vivo absorption rate, it is necessary to reproduce the conditions extant in the gastrointestinal tract following administration of the dosage form as possible. Adequate comparison of formulations for Class 2 drugs requires dissolution tests with multiple sampling times in order to characterize the release profile[7], and in some cases the use of more than one dissolution medium may also be worth considering.
Class 3 drugs are also defined as being rapidly dissolved as Class 1 drugs, then the test criterion should be that the formulation can release the drug under mild aqueous conditions within a predetermined time. Besides, the duration of the dissolution test should be at least as stringent for Class 3 drugs as for Class 1 drugs to try to maximize the contact time between the dissolved drug and the absorbing mucosa, and further the bioavailability of the compound.
As for Class 4 drugs, which are generally
considered poorly absorbed, special attentions should be paid on the formulation to avoid additional, negative influence on both the rate and extent of drug absorption caused by poor formulation.
Physicochemical factors affecting drug solubility and permeability
Solubility and intestinal permeability are the major physicochemical factors that affect the rate and extent of absorption of an oral drug product.
Moreover, these two factors also closely interrelate with many other influential factors, such as lipophilicity, hydrophilicity, molecular size, polar van der Walls surface area, and so on, and thus act as the
“final bridge” toward drug absorption. Therefore, making clear factors affecting solubility and permeability may be significantly important in drug product development and approval process for a large group of drug candidates.
Solubility
The first requirement for absorption is dissolution of the active compound. Only compound in solution is available for permeation across the gastrointestinal membrane. Solubility has long been recognized as a limiting factor in the absorption process. By definition, solubility is the extent to which molecules from a solid are removed from its surface by a solvent. Aqueous solubility can be estimated by determining the ability of a drug to partition from lipid to aqueous environments, which is dependent on the ionization of drug tested. Most drugs are weakly acidic or weakly basic compounds that cannot ionize completely in aqueous media, while only partly ionize. Since drug ionization are greatly dependent on the solvent pH, the above partition behavior is often considered as a function of solvent pH, and pKa is often used as a parameter describing a compound’s dissolution characteristic.
In general, ionized drugs tend to exhibit far greater aqueous solubility than the un-ionized counterpart.
As a result, the rate of solute dissolution in aqueous media can be markedly affected by the pH of the solvent.
To illustrate the effect of PH on drug ionization, one can seek to a rearrangement of the Henderson- Hasselback equation:[8]
Weak acid:
antilog(pH-pKa) =
[ionized]
[un-ionized]
that is:
% un-ionized = 100
1 + antilog(pH-pKa)
Weak base:
antilog(pKa-pH) =
[ionized]
[un-ionized]
that is:
% un-ionized = 100
1 + antilog(pKa-pH)
Weakly acidic drugs dissolve faster when solvent PH is relatively high(when more drug exists in its ionized form), while tend to have a slower dissolution rate at lower solvent pH (when more drug exists in its un-ionized form); on the contrary, weakly basic drugs dissolve faster when solvent pH is relatively low, and tend to have a slower dissolution at higher solvent PH. When solvent PH is equal to drug pKa, both weakly acidic drugs and weakly basic drugs exhibit the lowest solubility. Based on the above reason, by increasing the proportion of drug existing in its un-ionized state, meals that elevate gastric pH can decrease the dissolution of a weak base. For example, weak bases such as indinavir (with pKa of 3.7 and 5.9) are expected to precipitate when gastric PH is elevated during a meal, resulting in a significant reduction in AUC and Cmax values in fed versus fasted human subjects. Conversely, the same meal can increase the dissolution rate of a weak acid by increasing the proportion of drug existing in its ionized state, thereby making it more water soluble.[9]
Besides the above classic method using solvent pH and drug pKa to access drug solubility, several attempts have been made to estimate solubility from molecular structure, that is to find molecular properties that affect drug solubility. A compound’s aqueous solubility, as measured by its propensity to distribute between octanol and water, is a function of its ability to form hydrogen bonds with the water molecule. Generally, aqueous solubility is directly proportional to the number of hydrogen bonds that can be formed with water[10]. Delaney.[11] used linear regression against nine molecular properties. The most significant parameter calculated was logP(octanol), followed by molecular weight,
proportion of heavy atoms in aromatic systems, and number of rotatable bonds. The model performed consistently well across three validation sets, predicting solubilities within a factor of 5-8 of their measured values, and was competitive with the well-established “General Solubility Equation” for medicinal/agrochemical sized molecules.
Although lipid/water partitioning is often used to describe drug solubility, there is some evidence that solubility may better be described by the compound’s dynamic energy properties.[12] Determination of solubility parameter of a drug is a most common approach to quantify the cohesive energy for a drug, which is defined as the amount of energy required to separate the drug into its constituent atoms or molecules. The result showed that negative correlation was both evident between solubility parameter values and the extent of oral absorption, and between the number of H-bonding acceptor groups in a compound and the extent of oral absorption. Whereas, when ClogP values were used in comparison, no obvious correlation existed.
Permeability
Permeability is another important factor in achieving desirable oral bioavailability. The above critical property of permeability should contribute to the correspondingly unique way about how substances (including drugs) “travel through” cellular membranes. So to discuss physicochemical properties affecting permeability, one need first get to know the structure of cellular membranes and how drugs pass through these membranes (Fig 2).[13]
In the Fluid Mosaic model, the structure of cellular membranes is described as an interrupted phospholipid bilayer capable of both hydrophilic and hydrophobic interaction.[14] The two most common ways for the absorption of drugs are passive transfer by diffusion across the lipid membranes and passive diffusion through the aqueous pores at the tight junctions between cells. These two processes are referred to as transcellular and paracellular absorption, respectively. The ability of a drug to diffuse across the lipid core of the membrane is clearly dependent on physicochemical properties. Thus transcellular absorption is the predominant pathway for more lipophilic molecules. In contrast, the paracellular route of absorption is particularly important in determining the efficiency of absorption of hydrophilic compounds, the restricted diameter of the
aqueous pores(typically 3 to 6 Å in humans)means that molecular size also becomes important in the ability of polar molecules to utilize this pathway,
which is thought to be possible only for small hydrophilic molecules (MW < 200) [15,16,17].
Fig 2. GI membrane transport. The transport through the enteroyte barrier can be generally divided into active, passive and specialized transport and into a paracellular and transcellular route
Knowing about these particular characteristics of cellular membranes, several related factors of drugs such as lipophilicity, hydrophilicity, molecular size, polar van der Walls surface area and molecular flexibility and so on should be considered when accessisng drug permeability, modifying structure properties and finally designing more effective alternatives. Therefore the relationship between the above affecting properties and intestinal permeability are discussed as follows.
Because of the lipid nature of cell membranes, a molecule’s lipophilicity has long been considered as an important factor in drug design. Lipophilicity is generally quantified wexperimentally by measuring the log10 of the partition coefficient between n-octanol and water (log P). The relationship between log P and permeability is non-linear, with decreases in permeability at both low and high log P. These non-linearities are theorized to be due to: (1) the limited diffusion of poorly lipophilic molecules into the phospholipid cell membrane, and (2) the preferential partitioning of highly lipophilic molecules into the phospholipid cell membrane, preventing passage through the aqueous portion of the membrane[18].
Dynamic surface area properties also have effects on drug permeability. The polar surface area (PSA) of a molecule is defined as the area if its van der Walls surface thar arises from oxygen or nitrogen atoms or hydrogen atoms attached to oxygen or nitrogen atoms. The “dynamic” PSA (PSAd) is a
Boltzmann-weighted average value computed from an ensemble of low-energy conformers obtained by a detailed conformational search.[19] Palm K and co-workers[20] correlated the dynamic surface area properties of drug molecules with drug absorption.
Good inverse linear correlations between the dynamic polar surface area and permeability coefficients in monolayers of human intestinal epithelial Caco-2 cells and existed rat intestine were obtained, indicating that the dynamic polar surface area is an important factor in passive trans-cellular transport across cell membrane.
The hydrogen bonding ability of a molecule (an estimate of its hydrophilicity) is another important property for cellular membrane permeability. In Veber.
DF and co-workers’ study,[21] Hydrogen bond donors were taken as any heteroatom with at least one bonded hydrogen. Hydrogen bond acceptors were taken as any heteroatom without a formal positive charge. Higher oral bioavailability is found to be associated with lower hydrogen bond counts.
Besides, permeability is also affected by several other factors and is the function of multi-effects of all these factors. Specifically, higher oral bioavailability is indeed associated with lower molecular weight, which is a surrogate for other properties, such as polar surface area and hydrogen bond count, as well as rotatable bonds (defined as any single bond, not in a ring, bound to a nonterminal heavy atom). With the increasing of molecular weight, these properties also tend to increase.[21]
Also properties of the solute may have effects on drug permeability. Goodwin and co-workers[22]
demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability–limiting microenvironment within the cell depends on the properties of a special solute.
Physiological properties affecting drug absorption
The successful functioning of oral medication depends primarily on how the gastrointestinal (GI) tract processes drugs and drug delivery systems.
Many factors are involved in oral drug delivery, the measured oral bioavailability of a particular drug can be broken into components that reflect delivery to the intestine (gastric emptying, PH, food), absorption from the lumen (dissolution, lipophilicity, particle size, active uptake), intestinal metabolism (phase Ⅰ and/or phase Ⅱ enzymes), active extrusion (drug efflux pumps) and finally first-pass hepatic extraction.
All these factors play an important role in the performance of orally administered dosage forms, and to understand how they affect oral drug absorption can greatly contribute to the drug discovery process.
Principally, the rate of release of a drug from a dosage form within the GI tract should be considered.
Drug dissolution, especially for poorly soluble drugs, is dependent upon the volume of juices available in the gastrointestinal tract, which are from the volume of coadministered fluids, secretions and water flux across the gut wall[6]. The volume of intestinal juices is important to estimate if a single dose can theoretically dissolve within the gut passage.
Bile salts
The presence of bile may improve the bioavailability of poorly water soluble drugs by enhancing the rate of dissolution and/or solubility.
Bile salts can increase drug solubility via micellar solubilization. The increase in the rate of dissolution also may occur via a decrease in the interfacial energy barrier between solid drug and the dissolution media (via enhanced wetting), leading to an effective increase in surface area[23]. For example, in Galia E and co-workers’ study[24], dissolution of Class Ⅱ drugs (low solubility-high permeability) are proved to be in general much more dependent on the medium
(including the presence of bile salt) than class I drugs (high solubility-low permeability, such as dissolution of mefenamic acid from a capsule formulation is dependent on bile salt concentration. Bakatselou and co-workers[25] studied the ability of sodium taurocholate to increase the initial dissolution rate of five steroids (hydrocortisone, triamcinolone, betamethasone, and dexamethasone, danazol), the result showed that at bile salt concentrations representative of the fasted state, wetting effects predominated over solubilization effects for all compounds. While at the higher bile salt concentrations typical of the fed state, for the more lipophilic danazol, the increase in solubility was the predominant factor. Also the extent to which bile salts can enhance the solubility of a drug can be predicted based on the physicochemical properties of the compound, that is the increase in solubility as a function of bile salt concentration can be estimated on the basis of the partition coefficient and aqueous solubility of the compound.[26]
Gastric emptying and Intestinal transit time Furthermore, gastric emptying and GI transit time are important parameters for the onset and the degree of drug absorption. It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. The reason why the residence time is also a critical factor for drug absorption is that there is the site difference in absorbability for some drugs. Lipka and co-workers[27] demonstrated the significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to influence the occurrence of double peaks.Based on the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Oberle and co-workers[28] concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.
Marathe pH and co-workers[29] assessed the effect of
altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects.
Results showed that AUC(0,infinity) and UR% (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times, that is the extent of metformin absorption is improved when the gastrointestinal motility is slowed. Kimura and co-workers[30] using previously developed Gastrointestinal (GI)-Transit-Absorption Model in the prediction method for the plasma concentration-time profile of N-methyltyramine (NMT). Estimating permeability of each GI segment to NMT indicated that thiscompound is absorbed mainly from the small intestine and thatpermeability to NMT is largest in the duodenum and jejunum.
However, the contribution of this region to the total absorption in vivo is found to be small. The substantial absorption sites in vivo were suggestedto be the regions from lower jejunum to lower ileum, which have longerresidence time than duodenum and upper jejunum, thus the substantial absorption is a function of longerresidence time.
Liver metabolism
The liver is the major organ for drug metabolism, thus the prediction of human hepatic clearance is of great value in study factors affecting oral drug absorption. Lin and co-workers[31] provided an excellent discussion of factors that can affect the clearance, which can further affect the overall bioavailability of drugs. The hepatic clearance was described as follows:
CLH = (Qh・ fB・ CLint,h)/(Qh+ fB・CLint,h) EH = (fB・ CLint,h)/(Qh+ fB・CLint,h)
where Qh is the liver blood flow, CLint,h is hepatic intrinsic clearance, fB is the unbound fraction of drug in the blood, and EH is the hepatic extraction ratio, which is defined as the fraction of the drug entering liver that is metabolized during its transitthrough the liver. Therefore, only a portion (1-EH) of the dose passed through the liver will escape metabolism.
During drug absorption,the extraction ratio (EH) also is termed “first-pass” or “presystemic”elimination in liver, which is also take place in other organs, such as intestine.
Martinez and co-workers[32] transform the above equation to
CLH = Qh・E, and
E = [(fb・CLint)/(Qh + fb・CLint)]
when Qh>>fb·CLint,, then CLH = Qh ·[(fb·CLint)/(Qh+ fb·CLint)], which tends toward
fb・CLint・Qh / Qh = fb・CLint・1= fb・CLint
Conversely, when Qh << fb·CLint,, then CLH-Qh. For high E compounds, CLH is said to be blood flow limited (i.e., Qh<< fb· CLint,). In other words, CLH
will be affected by anything that can alter Qh (or Qh-splancnic for oral first-pass effects). In these cases, factors altering intrinsic clearance (CLint), such as drug-drug interactions, should have minimal impact on CLH. alternatively, for low E drugs, CLH-fb·CLint. in this situation, any factor that alter fb, Vmax, or KM
can markedly affect CLH. An example of these interrelationships is seen with the interaction between indinavir (oral or intravenous administration) and ketaconazole (oral administration).[33]
Intestinal Metabolism
It is also quite important to consider small intestine as a potential site of drug metabolism.
Substantial drug loss can occur via intestinal efflux mechanisms, gut wall metabolism (both PhaseⅠ and Phase Ⅱ), and the degradation within the gut lumen.
The cytochrome P450s (CYPs) are the major enzymes involved in the metabolism of drugs. Some of the CYP isoforms present in the liver are also expressed in the gut wall epithelium, the major one is CYP3A4, which in the small intestine approaches 50% of the hepatic level, and act as the major phase I drug metabolizing enzyme in humans. Both CYP3A4 and the multidrug efflux pump, MDR or P-Glycoprotein (P-gp), are present at high levels in the villus tip enterocytes of the small intestine, the primary site of absorption for orally administered drugs. These proteins are induced or inhibited by many of the same compounds and demonstrated a broad overlap in substrate and inhibit specificities, suggesting that they act as a concerted barrier to dug absorption[34]. Coadministration of cyclosporine with rifampin, an inducer of both CYP3A4 and P-gp, increases cyclosporine clearance, decreases its half- life, bioavailability (Foral) and Cmax. Conversely, ketoconazole, a CYP3A4 and P-gp inhibitor, decreases cyclosporine clearance, increases its half life, bioavailability (Foral) and Cma. [34]
Sinko and co-workers[35] performed a study in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion)
of saquinavir (SQV) mediated by P-gp and CYP3A.
In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged Cmax but prolonged Tmax and t(1/2), P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV.
Compounds may also be extensively metabolized in the gut lumen by digestive enzymes or by activity of the gut microflora. The former can decrease bioavailability of chloramphenicol[36] when administered in some species due to microbial degradation in the gut, while the presence of gut microflora may enhance drug bioavailabilty by promoting biliary recycling of compounds such as ouabain, digoxin, and steroid hormones.[37]
Food Effect
The effect of food on drug oral bioavailability is extremely complex. Based on the physicochemical properties of the compounds, physiological changes induced by the intake of food mainly happen in slowing of gastric emptying rate and the increase in gastric pH.
The pH differences in the contents of the upper GI tract between fed and fasted states can influence the dissolution and absorption of weakly acidic and basic drugs. Elevation of gastric pH following a meal may enhance the dissolution of a weak acid in the stomach but inhibit that of a weak base. Furthermore, food inhibits the rate of gastric emptying, prolonged retention in the stomach may increase the proportion of drug that dissolves prior to passage into the small intestine, which is the primary site of drug absorption.[23]
Elevated gastric pH may afford enhanced bioavailability of acid-labile drugs such as penicillin, erythromycin, and digoxin. For example, under acidic conditions, digoxin is hydrolyzed to the digoxigenin aglycone derivative, which has reduced pharmaco- dynamic activity.
For ionic drugs, the fraction of drug available for the absorption may be altered by changing pH values, thus affect the intestinal permeability of the drug. Besides, Ph changing can affect the dissolution
of some formulations, such as some coating materials used on tablets which are PH dependent, or some formulation excipients can also cause drug release to vary with pH, or impact on the permeability of insoluble film coatings used to provide controlled release of medicaments as well as on the overall dissolution and drug release patterns from various matrix-based sustained-release formulation.
Formulation Effect
The Noynes-Whitney equation describes the variables that can affect drug dissolution[38]:
dm/dt=(D·S/V·h)(Cs - Ct )
where dm/dt is the dissolution rate; D is the diffusion coefficient; S is the surface area; h is the thickness of the dissolution film adjacent to the dissolving surface;
Cs is the saturation solubility of the drug molecule; Ct
is the concentration of the dissolved solute; and V is the volume of the dissolution medium.
Among these factors, two variables that can be controlled by formulation are surface area and solubility. Increasing the surface area (S) of a drug particle can enhance the dissolution rate of the drug.
Drug particle size can be reduced to increase the effective surface area available for dissolution, which can be achieved by using wetting agents that lower the surface tension of the dissolution medium.
However, since the amount of the above surface-active agents needed to enhance in vivo drug dissolution rate may have effects on drug safety, these agents are not generally used in product formulations.[38] Drug particle is also important in determining the dissolution behavior of a drug. The shape factor for any non-isometric particle cannot be considered to be constant over the dissolution event, as is commonly assumed. This change has an appreciable effect on the dissolution behavior of crystals (particularly of significance for elongated shapes like needles and platelets)[39]. Sometimes modification of surface morphology of drug particle can improve its stability [40]. The solubility of weakly acidic and weakly basic drugs can be modified by using buffer agent to slightly change the surrounding pH. However, solubility differences between drug and buffer must be considered to avoid their relative dissolution rates preclude maintenance of the
“microenvironment” during the dissolution process.
Besides buffering agents, some excipients are known to have effects on physiological conditions, such as
decrease GI transit time[41], affect membrane permeability[42] and inhibit efflux pumps.[43,44]
Discussion
Drug absorption is a highly complex process, which is based on both physicochemical properties of the drug and physiological conditions of the body.
Therefore, in years scientists have been striving for improving the above two aspects to achieve desirable drug absorption, thus to screen out, optimize a large number of drug candidates and consequently promote drug development. In particular, solubility and permeability are the most important physicochemical properties affecting drug absorption; furthermore most other physicochemical properties (such as lipophilicity, pKa, molecular size, logP value, hydrogen bonding dynamics, and so on) are all correlated to solubility and permeability, and through their positive or negative effects on solubility and permeability to finally affect drug bioavailability.
Therefore, solubility and permeability can be considered to act as the “final bridge” toward drug absorption. On the other hand, physiological variables also can markedly affect the absorption characteristics of a drug. Generally drugs are absorbed in un-ionized state, which is dependent upon GI pH; also the changing of gastric emptying rate and intestinal transit time can affect drug absorption. Besides, drug may be metabolized by enzymes in liver and intestine, and by activity of the gut microflora. Therefore, the successful functioning of oral drug not only relates to the drug physicochemical properties, but also greatly dependent upon the delivery process in vivo, which is a function of many physiological factors. Moreover, pharmaceutists have been exerting to improve oral drug bioavailability through the invention and application of new formulations. However, improvement in formulation may also depend on their effects to physicochemical and physiological factors to affect drug absorption. Such as, increasing surface area of drug particle actually means changing its physicochemical properties, while the purposes of using some excipients and surfactants is to affect the physiological factors. Thus, by understanding the physicochemical properties of a compound and by recognizing the physiological processed affecting drug absorption, also with the awareness of a drug’s BCS characteristics, pharmaceutical scientists can
better predict drug absorption and develop formulations that can maximize drug bioavailability.
In this review, we discussed only some factors affecting drug absorption, physicochemical characteristics, physiological properties, formulation and food effects. Other factors, such as patient’s conditions, age, metabolism enzymes, administration time, drug interaction, and so on, are also affecting the pharmacokinetics in drug absorption. These factors will change the relationship between drug intake and clinical response.
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