Browsing by Subject "Bioavailability"
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Item Advanced formulation and processing technologies in the oral delivery of poorly water-soluble drugs(2013-08) Lang, Bo, 1986-; Williams, Robert O., 1956-With the advance of combinational chemistry and high throughput screening, an increasing number of pharmacologically active compounds have been discovered and developed. A significant proportion of those drug candidates are poorly water-soluble, thereby exhibiting limited absorption profiles after oral administration. Therefore, advanced formulation and processing technologies are demanded in order to overcome the biopharmaceutical limits of poorly water-soluble drugs. A number of pharmaceutical technologies have been investigated to address the solubility issue, such as particle size reduction, salt formation, lipid-based formulation, and solubilization. Within the scope of this dissertation, two of the pharmaceutical technologies were investigated names thin film freezing and hot-melt extrusion. The overall goal of the research was to improve the oral bioavailability of poorly water-soluble drugs by producing amorphous solid dispersion systems with enhanced wetting, dissolution, and supersaturation properties. In Chapter 1, the pharmaceutical applications of hot-melt extrusion technology was reviewed. The formulation and process development of hot-melt extrusion was discussed. In Chapter 2, we investigated the use of thin film freezing technology combined with template emulsion system to improve the dissolution and wetting properties of itraconazole (ITZ). The effects of formulation variables (i.e., the selection of polymeric excipients and surfactants) and process variables (i.e., template emulsion system versus cosolvent system) were studied. The physic-chemical properties and dissolution properties of thin film freezing compositions were characterized extensively. In Chapter 3 and Chapter 4, we investigated hot-melt extrusion technology for producing amorphous solid dispersion systems and improving the dissolution and absorption of ITZ. Formulation variables (i.e., the selection of hydrophilic additives, the selection of polymeric carriers) and process variables (i.e., the screw configuration of hot-melt extrusion systems) were investigated in order to optimize the performance of ITZ amorphous solid dispersions. The effects of formulation and process variables on the properties of hot-melt extrusion compositions were investigated. In vivo studies revealed that the oral administration of advanced ITZ amorphous solid dispersion formulations rendered enhanced oral bioavailability of the drug in the rat model. Results indicated that novel formulation and processing technologies are viable approaches for enhancing the oral absorption of poorly water-soluble drugs.Item Bioaccumulation and effects of metal contaminated soil on Great Plains toads, Bufo cognatus.(Texas Tech University, 2008-08) Bryer, Pamela Jean; McMurry, Scott T.; Cox, Stephen B.; Hooper, Michael J.; Carr, James A.Smelting and mining sites create local contaminated areas due to atmospheric release and deposition of metals and by increasing metal-enriched soil runoff. One of the proposed mechanisms of amphibian declines is contamination of habitats by chemical pollutants. Due to the number of mining and smelting sites worldwide, there is a risk to numerous amphibian populations from metal contamination. Currently, little is known about the effects of metal contaminated soil on amphibians. While it is generally understood that certain metals are highly toxic at low concentrations to most any organism, the exposure potential between organisms varies greatly. Metal uptake from soil is difficult to predict due to a complex metal-soil-water-toad relationship. Because of this complex relationship the use of models and passive sampling devices are not possible. This study consists of a series of soil exposures to toads Great Plains toads, Bufo cognatus. Each study follows the same basic design to assess metal bioaccumulation in toads housed individually on contaminated soil. The soils used in this study all came from or were created to mimic the soil conditions at the Anaconda Smelter Superfund Site, Deer Lodge County, MT, USA. The site is characterized by elevated levels of arsenic, cadmium, copper, lead, and zinc. Following their exposure, toads were tested through a series of behavioral, physiologic, and biochemical assays to asses the effects of the exposure. Between the studies, soil origin, soil temperature, size/age of the toads, and exposure duration were varied. Over the course of the studies, all metals showed increased bioaccumulation as soil metal concentration or exposure duration increased. Arsenic was not detectable in small, young-of-the-year toads. Cadmium concentrations, numerically, increased the most across each of the studies. Lead concentrations increased in most cases of increased exposure, however, variation in lead uptake in the adult toads studied was large as exposure duration increased. Zinc and copper tissue concentrations, both regulated essential metals, each increased with increasing exposure, however, zinc showed only slight to moderate increases overall. Partitioning within the body was highly variable between metals and between the studies. Overall, for juvenile toads, skin accumulated the bulk of the metals while in adults most metals accumulated in liver and kidney. One study compared the uptake of metals from soil collected at the Anaconda Smelter site to a series of spiked soils meant to mimic the ratio of metals in the Anaconda Smelter soil. Interestingly, we found that bioavailability was different between these soils, but not in the expected pattern. Cadmium and lead were both more bioavailable in the Anaconda Smelter soil than the spiked soil. Metal contaminated soil exposure had clear effects on the health of the toads. Time taken to bury was measured as a potential indicator of detecting contaminated soil avoidance, however, no differences were seen between soils. Although not consistent between each study the following endpoints were found to change in response to increasing soil metal concentration: prey orientating reflex, hop length, righting reflex, body mass, delta-aminolevulinic acid dehydratase (ALAD) activity, urine specific gravity, and mortality. Consistently across studies, organ (liver, kidney, and spleen) morphometrics did not change. It is clear, from this study and the works of others, that metal contaminated soil poses potential harm to amphibian populations. The effect of metal contaminated soil on toads can have two important ecological affects: 1) toads suffer directly from the presence of metal contaminated habitats and die, and 2) toads can accumulate metal concentrations that are then passed on via predation to other organisms in the food web. Protecting toads from metal contaminated soil is a challenge given their ability to bury deeply in the soil and their free ranging nature.Item Human Exposure to Foodborne Toxins in Ghana: Intervention Strategy for Reduction of Aflatoxin and Fumonisin Bioavailability(2013-08-30) Mitchell, Nicole JeanInternational health has typically focused on remediation of infectious diseases in developing countries. However, recent reports from the International Agency for Research on Cancer (IARC) have highlighted the importance of cancer incidence/ mortality in the developing world. Foodborne mycotoxins produced by fungi, called aflatoxin (AF) and fumonisin (FB), have been associated with hepatocellular and esophageal carcinomas among other deleterious effects, such as growth faltering and immune dysfunction. Exposure to these toxins in Ghana is particularly high due to food insecurity, climate, and lack of regulatory infrastructures. Work to alleviate AF and FB contamination in Africa has focused on instituting good agricultural and storage practices however, exposures remain inextricable in many communities. Utilization of a calcium montmorillonite clay, UPSN, shows promise of tightly binding both AF and FB in the gastrointestinal tract, thereby reducing their bioavailability. The objectives of this research were to determine exposure susceptibility in Ghana and to assess efficacy and safety of UPSN treatment within vulnerable populations. Cross-sectional data from six different regions of Ghana indicated that AF exposure is associated with maize consumption and region of residence. However, food preparation practices were not correlated to AF levels in the present study. Therefore, future intervention strategies were focused on the end point of the food consumption chain by reducing AF exposure from maize immediately prior to ingestion (i.e. UPSN treatment). In a three-month trial an encapsulated montmorillonite clay was efficacious in reducing AF exposure. However, concern for sustainability and its applicability for children led to an effort to alter the dose dissemination form. Inclusion of UPSN in common Ghanaian foods retained the efficacy of the clay, reducing a short-term biomarker (AFM_(1)) by 55%, and was determined to be safe in children (ages 3-9). Importantly, daily assessment of AFM_(1) levels was successful in providing statistical significance of intervention effects within only five days of treatment. Initial results indicate that UPSN could efficiently to bind both AF and FB in the gastrointestinal tract, reducing biomarkers for both toxins in animal models. Thus, UPSN could positively impact health in developing communities at risk for AF and FB exposure.Item Improved bioavailability and site specific delivery of poorly water soluble drugs through the production of stabilized drug nanoparticles(2005-08) Vaughn, Jason Michael; Williams, Robert O., 1956-Bioavailability enhancement of poorly water soluble active pharmaceutical ingredients (API) is key for improving existing therapies and allowing for formulation of certain new chemical entities. The rate limiting step for absorption of these APIs is dependent on the dissolution rate and the APIs apparent solubility. Particle engineering processes such as evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) were developed to enhance API dissolution and bioavailbality through the production of amorphous and nanoparticulate API. The morphology, primary API domain size and miscibility of particles produced by EPAS and SFL were investigated by several complementary and novel techniques. It was found that the SFL composition displayed amorphous character, a primary danazol particle size of 30 nm and was consistent with a solid solution. The EPAS composition was mostly amorphous with slight crystallinity, a primary danazol particle size of 500 nm and was consistent with a solid dispersion. The ability of the nanoparticulate and amorphous particles to supersaturate dispersions and how this impacts oral bioavailability was tested through in vitro and in vivo models. Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercial Danocrine® capsules. This improvement in solubility allowed for more danazol to be available for absorption in vivo. Pulmonary delivery of SFL nanoparticulate itraconazole was evaluated for pharmacokinetic parameters and steady state trough levels compared to oral delivery of an SFL oral composition and the commercial product. Inhalation of ITZ compositions is an effective method of antifungal therapy for the treatment and prophylaxis of invasive fungal infections. High and sustained lung tissue concentrations are achieved via inhalation of an amorphous ITZ pulmonary composition while maintaining serum levels which are above the minimum lethal concentration for A. fumigatus. Histology, macrophage uptake and IL-12 induction was evaluated for aerosolized amorphous ITZ nanoparticles. Pulmonary administration of amorphous ITZ nanoparticles or excipient placebo does not cause inflammation or changes in alveolar and airway histology. Uptake of ITZ by alveolar and airway macrophages occurs following inhalation of an amorphous ITZ composition.Item Improvement in the bioavailability of poorly water-soluble drugs via pulmonary delivery of nanoparticles(2009-08) Yang, Wei; Williams, Robert O., 1956-; Johnston, Keith P., 1955-High throughput screening techniques that are routinely used in modern drug discovery processes result in a higher prevalence of poorly water-soluble drugs. Such drugs often have poor bioavailability issues due to their poor dissolution and/or permeability to achieve sufficient and consistent systemic exposure, resulting in sub-optimal therapeutic efficacies, particularly via oral administration. Alternative formulations and delivery routes are demanded to improve their bioavailability. Nanoparticulate formulations of poorly water-soluble drugs offer improved dissolution profiles. The physiology of the lung makes it an ideal target for non-invasive local and systemic drug delivery for poorly water-soluble drugs. In Chapter 2, a particle engineering process ultra-rapid freezing (URF) was utilized to produce nanostructured aggregates of itraconazole (ITZ), a BCS class II drug, for pulmonary delivery with approved biocompatible excipients. The obtained formulation, ITZ:mannitol:lecithin (1:0.5:0.2, w/w), i.e. URF-ITZ, was a solid solution with high surface area and ability to achieve high magnitude of supersaturation. An aqueous colloidal dispersion of URF-ITZ was suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic ITZ levels when inhaled by mice. The significantly improved systemic bioavailability of inhaled URF-ITZ was mainly ascribed to the amorphous morphology that raised the drug solubility. The effect of supersaturation of amorphous URF-ITZ relative to nanocrystalline ITZ on bioavailability following inhalation was evaluated in Chapter 3. The nanoparticulate amorphous ITZ composition resulted in a significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation. In Chapter 4, pharmacokinetics of inhaled nebulized aerosols of solubilized ITZ in solution versus nanoparticulate URF-ITZ colloidal dispersion were investigated, under the hypothesis that solubilized ITZ can be absorbed faster through mucosal membrane than the nanoparticulate ITZ. Despite similar ITZ lung deposition, the inhaled solubilized ITZ demonstrated significantly faster systemic absorption across lung epithelium relative to nanoparticulate ITZ in mice, due in part to the elimination of the phase-to-phase transition of nanoparticulate ITZ.Item Influence of metal mixtures on co-occurring toxic metal bioavailability and effects in adult and developing deer mice(Texas Tech University, 2007-12) McBride, Tobias J.; Hooper, Michael J.; McMurry, Scott T.; Cox, Stephen B.; Hoff, Dale J.The bioaccessibility, bioavailability, and bioaccumulation of inorganic metals are complex principles. Unlike organic xenobiotics, many metals are required for biological functions. Nonetheless, dramatically increased concentrations of any metal may interact adversely with biomolecules, initiating a toxicological response when above a certain concentration in the organism. The bioavailability of environmental metals depends not only on metal concentrations in relevant matrices (food, water, soil), but on the chemical/physical form in which metals occur, the concentrations of other metals which co-occur, and the physiological status of the individual. Studies of mixed metal and metalloid (As, Cd, Cu, Pb and Zn) exposure in deer mice (Peromyscus maniculatus) at the Anaconda Smelter Site demonstrated that accumulation and biomarkers did not respond to the extent anticipated based on individual metal levels alone. This dissertation focuses on factors influencing the uptake, accumulation and resultant health effects of inorganic metals in a ubiquitous wild rodent species, and attempts to explain results from an earlier wildlife assessment on an NPL Superfund site. We sought to explain the variability in the effects of Pb exposure seen with the extreme heterogeneity of co-occurring metal contaminants in site soils. Using soil feeding studies, we have dissected the roles of Cu and Zn in modulating Pb absorption and Zn's role in reactivating ALAD activity in mice receiving high Pb doses. Second, our focus involves a lifetime bioaccumulation study of mice that investigated lactational metal exposure through the first 21 days of life (from soil-dosed feed provided to dams), and follows accumulation through 100 days of life. Comparisons with studies where adult mice were fed soil metals in their diet demonstrated that the more realistic lifetime exposure approach changes the accumulation kinetics, leading to greater accumulation of Cd and As, while underestimating exposures to Pb in the younger individuals. Finally, we investigate the role of lactation in weanling metal bioaccumulation, demonstrating how lactation decreases the dam's metal accumulation, while significantly increasing As and Pb exposure risks to the developing young.Item Nanoparticle formulations of poorly water soluble drugs and their action in vivo and in vitro(2007-12) Purvis, Troy Powell; Williams, Robert O., 1956-Poorly water soluble drugs have been manipulated to make them more soluble, increasing the bioavailability of these drugs. Several cryogenic processes allow for production of drug nanoparticles, without mechanical stress that could cause degradation. The Ultra Rapid Freezing (URF) process is a technique which improves water solubility of drugs by reducing primary drug particle size by producing amorphous solid dispersions. Heat conduction is improved, using a cryogenic material with a high thermal conductivity relative to the solution being frozen to maintain the surface temperature and heat transfer rate while the solution is being frozen. With URF technology, the freezing rate is fixed, which drives the particle formation and determines its characteristics. Supersaturation of drug in aqueous solution can allow for better absorption of the drug via the oral and pulmonary routes. Drug formulations that supersaturate the dissolution media show the possibility for increased bioavailability from an amorphous drug form. If the concentration of drug in solution is significantly increased, higher chemical potential will lead to an increase in flux across an exposed membrane, leading to higher blood levels for an amorphous drug, compared to an identical crystalline formulation. During oral delivery, supersaturated drug concentrations would also saturate PGP efflux sites in the gut lumen, increasing the drug's bioavailability. Saturated PGP sites show zero order efflux kinetics, so increasing the drug concentration in supersaturated biological fluid will increase serum drug levels. High supersaturation levels maintained for prolonged periods would have a beneficial effect on a drug's absolute bioavailability. Pulmonary administration offers therapeutic advantages over more invasive routes of administration. Limited amount of metabolizing enzymes like CYP 3A4 in lung tissue along with avoidance of first pass metabolism are advantages to pulmonary delivery. The objective of the research presented in this dissertation is to show the versatility of nanoparticulate poorly water soluble drug formulations. Due to the reduced particle size and the URF manufacturing process, a wide range of applications can be used with these nanoparticles. Oral and pulmonary administration routes can be explored using nanoparticles, but in vitro cell culture testing can show clinical benefits from this type of processing technology.Item Novel formulations and thermal processes for bioavailability enhancement of soluble and poorly soluble drugs(2013-12) Keen, Justin Martin; McGinity, James W.; Williams, Robert O., 1956-Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion (HME), have evolved rapidly. Several new technologies, specifically dry powder coating, injection molding, and KinetiSol® dispersing (KSD), have been adapted to the pharmaceutical arena. Co-rotating twin screw extrusion is routinely applied for the purposes of dissolving poorly soluble drugs into glassy polymers to prepare amorphous solid dispersions, which create supersaturated drug concentrations in the gastro-intestinal tract. A potentially more advantageous alternate geometry, counter-rotating twin screw extrusion was evaluated for preparation of model amorphous solid dispersion and was observed to be more efficient in forming a solid solution and reduced the thermal stress on the drug. HME and KSD processes were utilized to prepare two phase systems consisting of a lipid, glyceryl behenate, and a polymeric amorphous solid dispersion intended to provide both controlled release of drug and supersaturated drug concentrations in the release medium. Such systems are challenging due to the potential for crystallization of the drug within the dosage form during release, which was observed to be influenced by lipophilicity and porosity of the formulation, as well as the surface area to volume ratio of the system. High molecular weight cellulose based glassy dispersions were prepared using a weakly basic model drug by KSD, which when formulated into tablets were optimized to provide either immediate or approximately 2 hours of controlled release under the pH conditions simulating the environment of the stomach. Without formulation intervention in the external phase of the tablet, these compositions gel, muting drug release and missing the drug absorption window. Compositions optimized by an in vitro dissolution test were compared to a lower molecular weight HME prepared commercial product in a beagle dog model and observed to have statistically similar bioavailability, and in one case improved variability. A modified twin screw extrusion machine was utilized to develop a continuous granulation process capable of producing granules that do not require subsequent grinding or sizing. This novel process, which employs previously un-reported temperature profiles, produces lipid based granules that when compressed into tablets produce a controlled release of tramadol hydrochloride, which were not susceptible to alcohol induced dose dumping.Item Role of natural organic matter in governing the bioavailability of toxic metals to american oysters(Texas A&M University, 2006-08-16) Haye, Jennifer MarcelleColloidal macromolecular organic matter (COM), which makes up a large portion of the bulk dissolved organic matter (DOM) in marine environments, has the capability to modify the bioavailability of potentially toxic metals to aquatic organisms. In order to better understand the bioavailability of some of these metals to estuarine bivalves, American Oysters (Crassostrea virginica) were exposed to different types of natural colloidal (COM) and model (alginic acid, carrageenan, and latex particles) organic biopolymers, tagged with gamma-emitting radioactive metal ions (110mAg, 109Cd, 57Co, 51Cr, 59Fe, 203Hg and 65Zn) or 14C (to sugar OH groups). Natural COM was obtained from Galveston Bay water by 0.5??m filtration, followed by cross-flow ultrafiltration, using a 1kDa ultrafilter, diafiltration and freeze-drying. COM and DOM model compounds were used in the bioavailability experiments at 2 ppm concentrations. Separate 16-hour experiments using varying sizes of latex particles assessed the lowest size of colloids that can be filtered from the water. Results showed that filter-feeding bivalves could efficiently remove particles as small as 0.04??m (40nm) in diameter, with removal halftimes of 2.5 to 5.5 hours, equivalent to filtration rates of about 50??15 ml/hour, or about 3 L d-1 g-1, which are typical values for these oysters. Results of the 20-hour bioavailability experiments demonstrated that oysters could effectively filter metals bound to COM, with the metals bound to alginic acid COM being removed at the highest rates from the water. However, the metals bound to alginic acid were not found in oyster meat in the highest amounts: it was the metals associated with the carrageenan COM. The 14C labeled biopolymer data also showed alginic acid to be removed from the water at the highest rate and, contrary to the metals, was also present in the meat in the greatest amounts. Thus, while previous experiments suggested that the quantity (i.e., concentration) of natural organic matter is important for metal bioavailability, it was shown here that the ??quality??, i.e., the type of natural organic matter, is also a factor for controlling bioavailability, removal and incorporation rates of metals to oysters.Item Toxicity and bioavailability of explosive metabolites to invertebrates(Texas Tech University, 2006-12) Zhang, Baohong; Anderson, Todd A.; Cobb, George P.; McMurry, Scott T.; Cox, Stephen B.; Jackson, W. AndrewRDX and its N-nitroso metabolites were rapidly absorbed into earthworms. The BCFs were 1.86, 0.39, and 0.05 for RDX, MNX and TNX, respectively. It is unlikely that earthworms reduce RDX to MNX and MNX to TNX. Other biotransformation pathways may be involved in earthworm biodegradation of RDX. MNX and TNX were also absorbed by PSDs. Organic matter content is one soil factor that affected the ratio of MNX or TNX uptake into earthworms vs. uptake into PSDs. A linear relationship between PSD uptake and earthworm uptake was observed. These data indicate that C18 PSDs may be used as a surrogate for soil organisms such as earthworms and provide a simple and easy chemical test for assessing the bioavailability of contaminants in soils. MNX and TNX inhibited earthworm growth, caused death, and inhibited reproduction. Earthworms were more sensitive to TNX in sandy loam soil than other conditions. The LOLC for MNX and TNX was 100 mg/kg in sandy loam soil, and 200 mg/kg in silt loam soil. At 7 days of exposure, the LOEC for earthworm growth was 50 mg/kg for TNX and 100 mg/kg for MNX. After 35 days of exposure, earthworm growth was reduced 8-39% by TNX in sandy loam soil, whereas TNX only inhibited earthworm growth 5-18% in silt loam soil. MNX affected glutathione synthesis and the activity of GPX and ChE although no significant effects were observed on protein content, CAT, and GCS activity. Surprisingly, MNX enhanced ChE activity, especially the activity of AChE. AChE activity was enhanced more than 3-fold in earthworms exposed to 50 mg/kg MNX for 30 days. RDX N-nitroso metabolites, especially MNX, may cause oxidation stress in earthworms. MNX and TNX affected cricket egg hatching. TNX was more toxic to eggs than MNX. After 30 days exposure, the EC20, EC50, and EC95 were 47, 128, and 247 ìg/g for TNX, and 65, 140, and 253 ìg/g for MNX in topical tests and 21, 52, and 99 ìg/g for MNX, and 12, 48, and 97 ìg/g for TNX in sand. These data can be used for defining criteria for environmental management of RDX and performing specific risk assessment of RDX and its N-nitroso metabolites.Item Use of in silico predictors, solubility and permeability to select bioavailability and bioequivalence markers in herbal supplements(2007-12) Pade, Devendra Shrikant, 1972-; Stavchansky, SalomonDue to their rising popularity, herbal supplements have created a specific niche for themselves between the food and the drug industry. Due to their categorization as dietary supplements, they lack scientific seriousness where as on the other hand they act like unregulated drugs with potential effects. Finding scientific data of questionable accuracy for herbal supplements is not uncommon, which is usually designed to sell products rather then provide unbiased information. Hence, development of performance standards based on the bioavailability of the active components of herbal extracts promises to be an attractive solution towards regulating the inflow of meaningful products in the herbal supplement market. Solubility, partition coefficient and permeability are the fundamental properties for studying drug absorption. Top selling herbal extracts from the United States that included Kava, Ginkgo biloba, Milk thistle, Ginseng, Black cohosh, Garlic, Valerian, and Echinacea were selected and in silico descriptors such as CLogP, minimal cross-sectional area, polar surface area and in vitro permeability using the Caco-2 cell model and SimBioDAS® of their active components, determined. Based on the interparameter relationships between the minimal cross sectional area, CLogP, polar surface area and the in vitro permeability of the active components, bioavailability/bioequivalence markers were predicted for Kava, Ginkgo biloba and Milk thistle. Kawain was predicted as a marker for Kava, Ginkgolide B for the ginkgo terpenes and quercetin for the flavonol glycosides in Ginkgo biloba and silycristin as a marker for Milk thistle (silymarin). Silymarin comprising of isomers silycristin, silydianin, silybin A, silybin B, isosilybin A and isosilybin B was selected as a representative extract for further confirmation of marker prediction. Equilibrium solubility, experimental octanol-water partition coefficient values, and assay and in vitro dissolution profiles were determined for each of the active isomers in extract and market products respectively. The pharmacokinetics and absolute bioavailability of each of the active isomers was determined in male Sprague Dawley rats following intravenous and oral administration of the silymarin extract. Equilibrium solubility values indicated that all the silymarin isomers were practically insoluble, and silycristin and silydianin had relatively higher solubility values as compared to the other isomers. Experimental partition coefficient values correlated with the predicted partition coefficient (CLogP) with an r² of 0.834. Based on their equilibrium solubility and the partition coefficient (experimental and predicted) the active isomers were classified according to the Biopharmaceutic Classification System (BCS). Thus, isomers silybin A, silybin B, isosilybin A and isosilybin B were classified as Class II compounds (High PermeabilityLow Solubility) where as silydianin was classified as a Class IV compound (Low Permeability-Low Solubility). Silycristin was classified as a intermediate between Class II and Class IV. Absolute bioavailability (F) for silycristin was found to be the lowest (0.15±0.1), followed by silybin A (0.20±0.04) followed by silybin B (0.62±0.08). Silycristin being one of the least permeable and bioavailable component, was selected as a marker for silymarin, further confirming its prediction based on the correlations between the in silico descriptors and in vitro permeability. Pharmacokinetic parameters such as area under the curve, half life, volume of distribution, clearance and F for the components suggest significant differences between not only the silymarin isomers but also diastereomers of silybin (A and B) and isosilybin (A and B). Selection of bioavailability-bioequivalence markers, based on their least permeability/bioavailability, proves to be the most conservative and meaningful approach towards standardization of complex mixtures such as herbal extracts and supplements.