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is key Bioavailability



  • is key Bioavailability
  • Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability
  • 1. Introduction
  • In pharmacology, bioavailability (BA or F) is a subcategory of absorption and is the fraction of Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for. Bioavailability (biological availability) is a term used to describe the proportion of a nutrient in food that is . Enhanced bioavailability as a key aspect of synergy. Bioavailability is an essential measurement tool since it determines the correct dosage for non-intravenous administration of a drug. In clinical.

    is key Bioavailability

    Evidence suggests that a drug with high Log P will accumulate to a high concentration within the cytoplasmic membrane and favors binding to P-gp with low K m value, while a drug with low partitioning will have a lower membrane concentration and a high K m value. Three-dimensional structures of a large number of drugs revealed that the minimal common binding element consisting of two or three hydrogen bond acceptor HBA groups in a specific spatial distance. Since the TM sequences of P-gp are rich in hydrogen bond donor HBD groups, it is hypothesized that P-gp recognizes the HBA groups of the substrates through hydrogen bond formation in the lipid membrane environment Seelig , Seelig Although many such models describe the physicochemical attributes of P-gp interaction and are shown to have high predictability, existence of multiple binding sites and other complicating factors has prevented the development of a definitive SAR Stouch and Gudmundsson It is composed of amino acids with a MW of 72 kDa Graf et al.

    An atomic model of BCRP was predicted by homology modeling based on the crystal structure of the bacterial multidrug exporter Sav, which suggested that BCRP had multiple drug binding sites Hazai and Bikadi , Muenster et al. BCRP expression can be traced to placenta, kidney, liver, testis, brain, mammary tissue, and intestine Doyle and Ross Unlike P-gp, the expression of BCRP along the length of the small intestine does not vary significantly Bruyere et al.

    Since BCRP is highly expressed on the apical membrane of enterocytes and effluxing substrates back into the lumen, it has been noted to play an important role as a detoxification efflux transporter and limiting drug absorption in the GIT Zaher et al. In a clinical study, Kruijtzer et al.

    BCRP polymorphism significantly affects the pharmacokinetics of several HMG-CoA reductase inhibitors, including atrovastatin, rosuvastatin, fluvastatin and simvastatin lactone, but has no significant effect on pravastatin or simvastatin acid Bailey et al. Although, few clinical studies have been reported on the role of BCRP in the intestinal absorption, several studies using BCRP knock-out mice suggest significant impact Merino et al. Due to general selectivity, substrates of BCRP can be either negatively or positively charged, hydrophobic or hydrophilic, and unconjugated or conjugated.

    Also CPT analogues showed a good correlation between polarity and BCRP-association, where highly polar compounds showed substrate specificity. It is likely that the presence of hydroxyl and amino functional groups facilitate hydrogen bonding with the amino acid residues at the binding site of BCRP.

    BCRP substrate specificity of a set of pyrrolobenzodiazepine PBD derivatives showed a good correlation with the electrostatic potential and aromaticity Kaliszczak et al. Evidently, BCRP-mediated efflux could be circumvented by limiting C2 aryl substituents and the number of aromatic rings.

    In general, BCRP substrates share a same set of molecular properties as that of substrates to P-gp and other efflux pumps Begley , Kunta and Sinko , Takano et al. This enables the uptake of PepT1 transporter substrates to be coupled with the influx of protons back into the enterocytes Adibi The uptake of the PepT1 substrates is strongly dependent on the extracellular pH, where a pH of 4. These uptake studies suggested that the K m of glycylsarcosine Gly-Sar , a neutral substrate, decreased as the pH dropped from 7.

    The K m value of an anionic substrate, ceftibuten, declined steadily with a decreasing pH. Furthermore, the maximum transporter rate V max values gradually increased with a fall in pH from 7.

    The 3D structure of the substrate binding site of PepT1 is not yet known, but its template has been proposed by the large variety of substrates Foley et al. It is interesting to note that the peptide bond is not required for substrate binding specificity of PepT1 transporter Brandsch et al.

    Only the two oppositely charged free head groups carboxylic carbon and amino nitrogen separated by a 4 spacer carbon unit were identified as a minimal structural feature requirement Doring et al. In the presence of a peptide bond, it is only the backbone carbonyl that is functional. This minimal configuration also explains the efficient transport of -aminolevulinic acid, which serves as a precursor for the endogenous porphyrin accumulation on which photodynamic therapy of tumors is based.

    In addition, the side chains provided in both di and tripeptides and in xenobiotics with charge polarity and conformation are pivotal in determining the binding affinities. It should also be emphasized that for the di and tripeptides, only the trans-configuration of the peptide bond is transported. Besides a preferred free N-terminal amino group, a high electron density around the terminal carboxylic group in dipeptide, or alternatively around the carbonyl group of the second amino acid in a tripeptide structure, is needed to ensure optimum binding affinity.

    Furthermore, high electron densities at the first and third side chains, as well as the presence of hydrophobic side chains, significantly contribute to overall binding affinity Brandsch et al. Using PepT1 as an intestinal transporter to increase oral exposure of compounds with low oral bioavailability was shown to be an effective strategy Kikuchi et al.

    To overcome this limitation, valacyclovir, a L-valine ester prodrug of acyclovir was effectively designed to increase the oral absorption and plasma exposure of acyclovir Ganapathy et al.

    OATPs SLC O are transmembrane solute carriers that mediate the proton-dependent transport of a wide range of amphipathic endogenous and exogenous organic compounds across the plasma membrane. The OATPs represent integral membrane proteins that contain 12 TM domains where amino and carboxy termini are oriented to the cytoplasmic spaces.

    There is limited information regarding the tertiary structures of OATPs, although more recent studies are beginning to address this aspect.

    Similar to other OATPs, transport via OATP2B1 is generally considered to occur in a bidirectional fashion driven by the solute concentration gradient across the membrane. Extracellular acidification promoted solute uptake, a property of OATP2B1 that bears relevance to the small intestinal environment in which the transporter is expressed on the apical membrane of the enterocytes.

    The group reported that the uptake of both compounds were pH dependent, where higher uptake at pH 5. It is interesting to note that an increase was only observed in V max with a decrease of pH from 7. The results indicated that OATP2B1-mediated transport is significant for rosuvastatin, fluvastatin and atorvastatin, at neutral pH. Furthermore, uptake at acidic pH was diminished in the presence of proton ionophore, suggesting proton-gradient as the driving force for OATP2B1 activity.

    Notably, passive transport rates are predominant or comparable to active transport rates for statins, except for rosuvastatin and fluvastatin. Second, we studied the effect of OATP modulators on statins uptake.

    The present results indicate that OATP2B1 may be involved in the tissue uptake of rosuvastatin and fluvastatin, while OATP2B1 may play a significant role in the intestinal absorption of several statins due to their transporter affinity at acidic pH. The physiological and pharmacological role played by OATP2B1 in intestinal absorption may also vary between individuals. These models have demonstrated good structure and activity correlation within the studied chemical space.

    The proposed OATP2B1 pharmacophores may share the similar molecular features for the consideration of the substrate binding at the positively-charged region. To model these interactions structurally using molecular docking and dynamics, the minimal requirement will be a validated homology model of OATP2B1.

    This transporter consists of amino acids and is expressed in the brain, kidney and apical membrane of the enterocytes Kullak-Ublick et al. It has been reported to transport bile salts and bromosulfophtalein BSP , steroid sulfates, thyroid hormones [triiodothyronine T3 , thyroxine T4 , and reverse T3], prostaglandin E2, fexofenadine, opioid peptides [e.

    For example, Lee et al. GluAsp variant had markedly reduced uptake capacity for the OATP1A2 substrates estrone 3-sulfate and the d-opioid receptor agonists, deltorphin II and [D-penicillamine2,5]-enkephalin in vitro. The group concluded that considering its substrate specificity and expression in organs such as the brain, kidney and intestine, genetic variations in SLCO1A2 may be an important contributor to inter-individual variability in drug disposition and central nervous system entry of OATP1A2 substrate drugs Lee et al.

    In the clinic, the effect of grapefruit juice on the oral exposure of fexofendadine was evaluated. Similar findings were reported in a study that evaluated the effect of single and repeated grapefruit juice ingenstion on the oral plasma exposure of talinolol in humans.

    The bi-directional movement of monocarboxylic acids across the plasma membrane is catalyzed by a family of proton-linked monocarboxylate transporters MCTs. MCTs are encoded by the SLC16A gene family, of which there are 14 known members that were identified through screening genomic and expressed sequence tag databases Halestrap and Meredith Only MCTs have been shown to catalyze the proton-coupled transport of metabolically important monocarboxylates such as lactate and pyruvate Halestrap and Meredith MCT1 is expressed in most tissues and is especially prominent in the heart, red skeletal muscle, erythrocytes, and all cells under hypoxic conditions, where it can either be involved in the uptake or efflux of glycolytically produced lactic acid.

    MCT1 is also highly expressed in the small and large intestine Gill et al. MCT1 catalyses the facilitative diffusion of substrate across the plasma membrane, coupled with the translocation of a proton.

    Based on the reported crystal structures of two members of the major facilitator superfamily, the Escherischia coli glycerolphosphate transporter G1pT and lactose permease Lac Y Abramson et al. Futhermore, site-directed mutagenesis identifying key substrate-binding residues together with structural modeling has lead to the suggestion of a translocation cycle as the mechanism of transport for MCT1 Wilson et al. This model describes MCT1 existing in an open and closed conformation, with the N- and C-terminal halves tilting against each other along an axis that separates the two domains, allowing the substrate binding site alternating access to the either side of the membrane Wilson et al.

    MCT1 also requires an ancillary protein, CD, for correct trafficking to the plasma membrane as well as functional activity Wilson et al. The targeting of MCT1 by pharmacologically active drugs has been shown to result in enhanced intestinal drug uptake.

    XP is an anionic compound produced by the reversible modification of the amine group of gabapentin which has limited oral absorption , with an acyloxyalkylcarbamate promoeity Cundy et al. Overall, prototypical substrates of MCT1 generally consist of weak organic acids with the carboxyl group attached to a relatively small R group containing lipophilic or hydrophilic properties Enerson and Drewes Our group recently investigated the interrelation of physicochemical properties and individual parameters for a database comprised of Fa, Fg, Fh, and F values for drugs in humans Varma et al.

    The aim is to define the physicochemical space for optimum human oral bioavailability. The current data set indicated that bioavailability is mainly limited by absorption as evident from the subset of compounds showing bioavailability less than 0.

    The distribution of the data set in physicochemical space is heterogeneous and thoroughly covered the range of conventional small molecule marketed drugs. Trend analysis clearly indicate that ionization state, molecular weight MW , lipophilicity, polar descriptors, and free rotatable bonds RB influence bioavailability.

    For example, ionization state analysis of compounds studied indicate that although bases tend to have higher Fa, they are relatively less bioavailable as compared to acids and neutrals. The scholarship outlined above is consistent with the finding of Lipinski et al, who introduced the rule of 5 RO5 , which is one of the most widely used concepts to qualitatively predict oral drug absorption. Poor bioavailability is more likely when the compounds violate two or more of the RO5.

    Using the current data set, we evaluated the relationships between number of violations and bioavailability and the individual processes. From Figure 1 , it is evident that median bioavailability dropped considerably from 0. Compounds with three violations showed a further decline in median bioavailability 0.

    However, similar relationship was observed only with Fa but not with Fg and Fh, suggesting that relationship of rule-of-five and bioavailability is associated mainly with intestinal absorption.

    Drug dissolution rate is an important parameter that affects oral drug absorption Chaumeil , Boobis et al. A drug is defined as being poorly soluble when its dissolution rate is so slow that dissolution takes longer than the transit time past its absorptive sites, resulting in incomplete oral absorption.

    Where DR is the dissolution rate, A is the surface area available for dissolution, D is the diffusion coefficient of the drug, h is the thickness of the boundary diffusion layer adjacent to the dissolving drug surface, C s , is the saturation solubility of the drug in the diffusion layer, C is the concentration of the drug in the bulk solution at time t.

    As shown in the equation above, the drug dissolution rate is directly proportional to the surface area of the drug particle, which in turn is increased with decreasing particle size. This can be accomplished by micronization or by the use of nanosuspension to reduce the particle size of the drug and therefore increases drug dissolution rate, which usually is associated with an increase in the extent as well as rate of oral absorption Chaumeil , Li et al.

    Examples on a drug for which reducing its particle size had significant impact on its dissolution rate is griseofulvin. Measurement of the amount dissolved in water versus time using a micronized powder showed that the rate of dissolution depended on the area of contact, which is related to the particle size. Relationship between number of violations of rule-offive and bioavailability and individual processes. As noted above, many drug molecules can be classified as either weak acids or bases that tend to form strong ionic interaction with an oppositely charged counter-ion and maintain that interaction through crystallization.

    The resulting solid comprises charged drug molecules and their associated oppositely charged counter-ions and is usually referred to as salt.

    The use of salt forms as active pharmaceutical ingredients is well established in the literature Berge et al. A salt form of a drug molecule changes the coulombic attraction between the drug molecule and its counterion and alters the potential energy of the solid state. This is usually associated with alteration of the pH of the diffusion layer at the surface of the dissolving solid, and therefore significantly increases the solubility of the parent drug molecule C s , in that layer over its inherent solubility at the pH of the dissolution medium C.

    In general, these changes can result in a significant increase in the dissolution rates and higher apparent solubility of the drug molecules in physiologically relevant timescales.

    Overall, if other relevant factors such as chemical stability, permeability, intestinal and liver metabolism remain constant, the dissolution rate of a compound should determine the rate of build-up of blood levels with time and the maximal levels achieved Nelson , Chowhan , Hendriksen et al. In summary, the drug salt form usually alters the drug dissolution rate by modifying the diffusion layer pH at the surface of the dissolving solid Nelson In fact, the rank order of dissolution rates of theophylline was closely correlated with the clinical blood exposure.

    This report led many additional studies that demonstrated the influence of the salt form on drug dissolution and the benefit of changing nonionized drug to salts Nelson , Nelson , Berge et al. Polymorphs of a drug substance are chemically identical. However, due to the differences in their molecular packing, they have different physical properties such as crystal shape, molecular density, melting temperature, hygroscopicity, and enthalpy of fusion Huang and Tong , Li et al.

    Albeit these differences, the various polymorphs tend to have comparable solubility profile. Pudipeddi and Serajuddin evaluated the effect of various polymorphs of drug molecules reported in the literature on their solubility profiles. The group reported that the solubility values of various polymorphs for these drug molecules did not differ more than two-folds. This difference in the solubility value is not expected to have profound impact on the compound biopharmaceutical profile depending on the doses used, particle sizes, and solubility values Pudipeddi and Serajuddin However, polymorphism may influence the physical and chemical stability of various drug molecules by influencing the rate and mechanism of decay Cohen and Green , Matsuda et al.

    Examples are carbamezepine Matsuda et al. There are significant differences between crystalline polymorphs and the amorphous form of a drug.

    In general, the amorphous form tends to have significantly higher dissolution rate and solubility compared to their crystalline forms, which may significantly increase their rate and extent of oral absorption. However, the amorphous form is generally less chemically stable due to the lack of a three dimensional crystalline lattice, higher free volume, and greater molecular mobility. The chemical stability of amorphous systems has been discussed in detail elsewhere Craig et al.

    The drug complexes of interest are generally divided into two major categories based on the energy of attraction between the components of the complexes. Examples on covalently linked complexes are prodrugs that are prepared by chemical modification of the drug through the addition of a labile moiety, such as ester group Van Gelder et al.

    The labile groups are usually broken by enzymatic action, and the parent drug is freed to produce its pharmacological action. The prodrug approach has been widely used in the development of bacampicillin, chloramphenicol, pivampicillin, and enalapril Van Gelder et al. Inclusion compounds, which form the second category of complexes, result more from the architecture of molecules than from their chemical interaction.

    One of the constituents of the complex is trapped in the cage-like molecular structure of the other to yield a stable arrangement. Cyclodextrins have been most widely used for this purpose, since they can trap lipophilic drugs in their molecular envelope and form a complex having a comparatively more hydrophilic character Shimpi et al.

    It is well established in the literature that a complex formation of a drug with cyclodextrin is known to improve drug solubility or dissolution rate, and thereby its oral bioavailability Irie and Uekama , Loftsson et al. It should be stressed that the drug molecules can also form complexes that may adversely affect their oral bioavailability.

    One widely reported example is the complexation of tetracycline with aluminum, calcium, or magnesium ions to form an insoluble complex that cannot be absorbed Kakemi et al. Before the complexation phenomenon was known, the administration of antacids with tetracycline was suggested to minimize the gastrointestinal disturbance nausea and vomiting caused by the antibiotic Gugler and Allgayer However, complexation can also arise due to the calcium ions present in milk and other dairy products Jung et al.

    Solubility and permeability are the fundamental properties determining the bioavailability of an orally active drug. Based on these properties Amidon et al. This concept exploring dose number, dissolution number, and absorption number of an orally administered drug clearly dictate its systemic availability. The US FDA, other regulatory agencies, and healthcare organizations have implemented the BCS to enable the use of in vitro solubility and permeability data to waive conducting expensive bioequivalence clinical studies BE of high solubility-high permeability Class I drugs.

    While the pharmaceutical industry has taken advantage of BCS-based biowaivers, its principles are used throughout the drug discovery and development to drive oral active programs. On the basis of the apparent correlation between intestinal permeability rate and extent of drug metabolism, Benet and coworkers proposed biopharmaceutics drug disposition classification system BDDCS , and suggested that the extent of drug metabolism may be used for characterizing high intestinal permeability drugs Wu and Benet , Benet Small intestine has an ability to metabolize drugs by several pathways involving both phase I and phase II reactions and may lead to limited oral bioavailability.

    CYP3A4, the most abundant cytochrome P present in human hepatocytes and intestinal enterocytes is implicated in the metabolic elimination of many drugs Paine et al. It has also been proposed that drug interactions involving CYP3A inhibition and induction may be largely occurring at the level of the intestine Hebert et al. The intestinal first-pass metabolism in humans is indirectly estimated under certain assumption, by comparing the plasma AUCs following intravenous and oral dosing.

    Early studies in liver transplant patients during the anhepatic phase indicated the relative importance of the gut extraction to the first-pass metabolism for drugs such as midazolam and cyclosporine Paine et al. Further clinical evidences were obtained in the grape-fruit juice interaction studies, where coadministration of grape-fruit juice result in the inhibition of gut CYP3A4 without significantly affecting the hepatic metabolism of drugs like felodipine Gertz et al.

    However, assessment of the quantitative contribution of intestinal and hepatic extraction in first-pass metabolism is limited by ethical and technical challenges. There exist gaps in predicting the gut extraction before the clinical development stage due to shortcomings in the in vitro-in vivo extrapolation Eg. Also species differences exist where rat and monkey typically under-predicts the fraction escaping gut extraction Fg in human Cao et al. Recently, transgenic mice model with constitutive expression of human CYP3A4 in liver or intestine that provides quantitative estimation of the contribution of hepatic and gut extraction to the first-pass metabolism has been generated van Waterschoot et al.

    Overall, due to limited access to the sophisticated models and complexities with in vitro in vivo extrapolation and species differences, intestinal metabolic disposition is far from consistently predictable.

    Recent studies demonstrated that efflux transporters present on the apical membrane of enterocytes, in particular Pgp, can affect the intestinal metabolism by prolonging the enterocytic transit time and consequent exposure to CYP3A enzymes Wacher et al.

    A significant overlap has also been identified between substrates and inhibitors of CYP3A4 and Pgp, suggesting that these two proteins may act complementarily in further limiting Fg of CYP3A substrates. Due to the complexity in these biochemical processes and the lack of availability of extensive experimental models, application of physiologically-based pharmacokinetic PBPK models and systems biology seem to provide quantitative prediction of first-pass metabolism.

    These emerging tools aim towards appropriate reconstruction of the physicochemical, anatomical and biochemical complexities in mathematical terms. Bioequivalent products are expected to be therapeutically equivalent. Therapeutic nonequivalence eg, more adverse effects, less efficacy is usually discovered during long-term treatment when patients who are stabilized on one formulation are given a nonequivalent substitute. Sometimes therapeutic equivalence is possible despite differences in bioavailability.

    For example, the therapeutic index ratio of the minimum toxic concentration to the median effective concentration of penicillin is so wide that efficacy and safety are usually not affected by the moderate differences in plasma concentration due to bioavailability differences in penicillin products.

    In contrast, for drugs with a relatively narrow therapeutic index, bioavailability differences may cause substantial therapeutic nonequivalence.

    See also Overview of Pharmacokinetics. Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver; both are common sites of first-pass metabolism metabolism that occurs before a drug reaches systemic circulation.

    Thus, many drugs may be metabolized before adequate plasma concentrations are reached. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.

    Insufficient time for absorption in the GI tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane eg, if it is highly ionized and polar , time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, physical activity, genetic phenotype, stress, disorders eg, achlorhydria, malabsorption syndromes , or previous GI surgery eg, bariatric surgery can also affect drug bioavailability.

    Chemical reactions that reduce absorption can decrease bioavailability. They include formation of a complex eg, between tetracycline and polyvalent metal ions , hydrolysis by gastric acid or digestive enzymes eg, penicillin and chloramphenicol palmitate hydrolysis , conjugation in the intestinal wall eg, sulfoconjugation of isoproterenol , adsorption to other drugs eg, digoxin to cholestyramine , and metabolism by luminal microflora.

    Bioavailability is usually assessed by determining the area under the plasma concentration—time curve AUC—see Representative plasma concentration—time relationship after a single oral dose of a hypothetical drug.

    AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation. Drug products may be considered bioequivalent in extent and rate of absorption if their plasma concentration curves are essentially superimposable.

    Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

    Drug Bioavailability and Clinical Pharmacology - Learn about from the MSD Manuals thus, knowing whether drug formulations are equivalent is essential. Learn how to maximize your body's ability to absorb curcumin and achieve its maximum health-promoting effects. Bioavailability By: Aditya Arya. Pharmacokinetic Studies Key Measurements • AUC – Area under the concentration- time curve • Cmax.

    1. Introduction



    Drug Bioavailability and Clinical Pharmacology - Learn about from the MSD Manuals thus, knowing whether drug formulations are equivalent is essential.


    Learn how to maximize your body's ability to absorb curcumin and achieve its maximum health-promoting effects.


    Bioavailability By: Aditya Arya. Pharmacokinetic Studies Key Measurements • AUC – Area under the concentration- time curve • Cmax.


    Bioavailability is key from a nourishment perspective as our body gets a greater amount of the available supplements when the supplements.


    Bioavailability of trace minerals in dairy cows usually refers to an essential trace mineral source that is consumed, digested and absorbed by.

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