Many candidate agents fail during clinical testing because of their unfavorable pharmacokinetic properties, unacceptable adverse effects, excessive toxicities, or the lack of efficacy. A key to the success of synthesizing molecules through the research and development process is the possession of desirable properties such as an adequate solubility, an ability to cross critical membranes (the intestinal and, sometimes, the blood-brain barrier), reasonable metabolic stability, and safety in humans. Depending on the therapeutic area being investigated, it might also be desirable to avoid certain enzymes or transporters to circumvent potential drug-drug interactions. It may also be important to limit the induction of further toxicities.

For a drug to reach target cells, it must first be absorbed by the body, most often through the blood stream first. Three parameters that measure the absorption of a compound are: solubility, stability, and the n-octanol/water partition coefficient. The n-octanol/water partition coefficient (LogP) indicates how a compound enters nonpolar regions of the body such as fat and cell membranes. It is an important indicator of drug permeability. The blood-brain barrier can be a serious obstacle for brain targeting drugs. Absorption critically determines the drug's bioavailability, meaning the fraction of an administered dose of unchanged drug that reaches the systemic circulation. There are a few in vitro permeability assays including the use of synthetic lipophilic membranes, Caco-2 and MDCK (Madin-Darby canine kidney) cell monolayers. Other methods include immobilized artificial membrane columns and human serum albumin columns.

After a drug is absorbed into the blood stream, it rapidly circulates through the body. The average circulation time of blood is 1 minute. As the blood circulates, the drug moves from the blood stream into the tissues. Most drugs do not spread evenly throughout the body. Water-soluble drugs tend to stay within the blood and the interstitial space between the cells. Fat-soluble drugs tend to concentrate in fatty tissues. Some drugs accumulate in certain tissues which have high affinity to certain drugs. Factors affecting distribution rate, such as blood flow rate and membrane permeability, and factors affecting distribution extent, such as tissue properties, pH values, and plasma protein binding all contribute to drug distribution. Drug characteristics affect both distribution rate and extent.

Drugs begin to break down as soon as they enter the body. Although some drug metabolites are pharmacologically more active, drug metabolism is generally a detoxification process in which a drug is converted to polar metabolites that can be eliminated more easily from the body. Drug metabolism, mostly occurring in liver, can be divided into phase I and phase II reactions. Phase I reactions occur before phase II reactions and involve oxidation, reduction, hydrolysis, cyclization, or decyclization reactions. Oxidation is the most common phase I reaction and it involves the heme-containing cytochrome P450, NADPH, and oxygen. Following phase I reactions, many metabolites are polarized enough to be excreted. Metabolites that are not sufficiently polar may undergo phase II metabolism which involves conjugation with large molecular groups that further reduce the biological activity of the metabolite (if any). Conjugation occurs with glucuronic acid, sulfonates, glutathione, or amino acids. Functional groups that are often attached to these large molecules include carboxyl, hydroxyl, amino, and sulhydryl groups. SABiosciences' Drug Metabolism and Drug Metabolism: Phase I Enzymes PCR arrays can be used to detect the drug metabolism abnormality via gene expression analysis.

Drug can be excreted into urine, bile, saliva, gut, alveolar, milk, sweat, and tears. The kidney is the principle organ of drug excretion. Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. Most drug transporters can be classified into two superfamilies: the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily. ABC drug transporters largely contribute to multiple drug resistance. Bacterial resistance to antibiotics and tumor resistance to anti-cancer drugs are two manifestations of multiple drug resistance. ABCB / MDR / P-glycoprotein, ABCC / MRP, ABCG2 / breast cancer resistance protein / BCRP, and lung resistance protein / LRP / major vault protein / MVP are the major players in multiple drug resistance. You can use SABiosciences' Drug Transporters and Cancer Drug Resistance and Metabolism PCR arrays for your studies.

Many drugs, especially most cancer chemotherapeutic drugs, damage DNA. The major forms of DNA damage include single-strand breaks (SSB), double-strand breaks (DSB), alteration of bases, hydrolytic depurination, hydrolytic deamination of cytosine and 5-methylcytosine bases, formation of covalent adducts with DNA, and oxidative damage to bases or to the phosphodiester backbone of DNA. DNA damage is caused by five main types of reactions: oxidation, alkylation (usually methylation), hydrolysis of bases, bulky adduct formation, and mismatch of bases due to DNA replication errors. The vast majorities of these lesions are repaired through base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) mechanisms. In BER, the damaged base is removed by a DNA glycosylase, resynthesized by a DNA polymerase, and a DNA ligase performs the final nick-sealing step. NER recognizes bulky, helix-distorting lesions. Both NER and MMR involve the recognition of damaged DNA, removal of the damaged DNA, and deployment of various repair proteins and enzymes. SABiosciences provides DNA Damage Signaling Pathway PCR array to help you analyze DNA repair mechanisms.

Heat shock, oxidative stress, and endoplasmic reticulum (ER) stress are three other major forms of cellular stress. The expression of heat shock proteins can be increased by stress such as infection, inflammation, exercise, exposure to toxins, starvation, hypoxia, or water deprivation. Consequently, the heat shock proteins are also referred to as stress proteins and their upregulation is part of the stress response. Conditions interfering with the function of the ER are collectively called ER stress. ER stress is induced by accumulation of unfolded protein aggregates or by excessive protein traffic usually caused by viral infection. Chaperones are proteins that assist proper protein folding. Many chaperones are heat shock proteins because protein folding is severely affected by temperature. SABiosciences provides Heat Shock Proteins and Unfolded Protein Response PCR arrays to detect cellular stresses on the gene expression level.

Oxidative stress occurs when the generation of reactive oxygen species (ROS; also called free radicals) in a system exceeds the system's ability to neutralize or eliminate them. ROS can damage DNA, RNA, lipids, and proteins. Oxidative damage therefore has been implicated in the cause of many diseases such as cancer, diabetes, neurodegenerative, and cardiovascular diseases and affects aging. The brain is extremely susceptible to oxidative damage due to its high lipid content and oxygen consumption. The transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes which encode proteins responsible for detoxication of electrophiles and reactive oxygen species (ROS) as well as the removal or repair of their damaging effects and products. Mitochondria are a primary site of production of free radicals. While more than 98% of the molecular oxygen taken up by cells is fully utilized by cytochrome c oxidase to form water, this enzyme also can release free radicals. Other enzymes of the respiratory chain, in particular complexes I and III, also produce ROS. Mitochondrial ROS have become targets for drug discovery in recent years since their production is characteristic of early stages of apoptosis. Superoxide dismutase 2 (SOD2) is a key mitochondrial enzymatic antioxidant. Mice lacking SOD2 die within the first week of life due to mitochondrial dysfunction and oxidative stress. Tumor suppressor protein p53 is a master transcription factor that organizes cellular responses to a variety of stresses. ROS act as both an upstream signal that triggers p53 activation and a downstream factor that mediates apoptosis. Direct detection of ROS and other free radicals is difficult because these molecules are short-lived and highly reactive in a nonspecific manner. SABiosciences' widely used Oxidative Stress & Antioxidant Defense PCR array can be deployed to analyze oxidative stress in the research model of your choice. Stress and Toxicity PathwayFinder PCR array can help pinpoint the mechanism of toxicity.