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Bioenergetics
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Glycolysis can be stimulated by ammonia, Pi, ADP, and pH and is very strongly stimulated by AMP and an increase in the AMP:ATP ratio, which is associated with fall in energy charge (35, 237, 270). Glycolysis is inhibited by markedly lowered pH, ATP, and a decreased AMP:ATP ratio, PCr, citrate, and free fatty acids (FFA) (35, 116, 171, 237). Primary control of glycolysis is a result of the glucose phosphorylation (G–6-P) by hexokinase (35, 161, 171). The rate of glycogen breakdown catalyzed by phosphorylase also must be considered (35, 223, 231) as this provides a readily available supply of glucose. The primary rate-limiting step for glycolysis is control by PFK:
Bioavailability and Granule Properties
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Following the administration of a drug through a solid dosage form, a sequence of steps is required before the drug reaches the systemic circulation. As shown in Figure 22.2, an orally administered solid dosage form undergoes disintegration and deaggregation, followed by the dissolution of the drug. The dissolved drug molecules must penetrate the gastrointestinal membrane and reach the general circulation. Each of the steps involved may limit how fast the drug molecules reach the general circulation and, therefore, the site of action. The step that offers the maximum resistance is referred to as the rate-limiting step. Which step will be rate-limiting, on the other hand, will depend on the physicochemical properties of the dosage form and the physiology of the gastrointestinal tract. The focus of the discussion here, however, will be on the physicochemical properties of the dosage form.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Two enzyme systems are involved in the metabolism of alcohol; one is cytosolic, and the other is microsomal. Alcohol and aldehyde dehydrogenases are cytosolic components mainly responsible for the first two steps of alcohol oxidation.57,233,288,544 The second alcohol oxidizing enzyme complex is bound to the microsomal fraction.36,549 Alcohol dehydrogenase is found mainly in the liver. This enzyme is the rate-limiting step in the metabolism of alcohol (Figure 34). In the human liver, there are three to seven active alcohol dehydrogenase isoenzyme fractions with variable activity.280,565,610 The isoenzymes composition varies widely from and with different turnover rates, thus explaining the individual and ethnic variations. Aldehyde dehydrogenase is present in many tissues,564 and several isoenzymes have been identified.234,246,425,474 Animal experiments have shown that with alcohol pretreatment the activity of alcohol dehydrogenase increases. This adaptive change may be important in the development of tolerance in alcoholism.
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Hexokinase catalyzes the phosphorylation of glucose into glucose-6-phosphate (G6P) by transferring a phosphate group from ATP to glucose, which is the first committed and rate-limiting step of glycolysis [10]. Among its four isoforms, Hexokinase 2 (HK2) is the uppermost isoform in insulin-sensitive tissues, such as heart, skeletal muscle, and adipose tissues in mammal [11]. It has also been found to be upregulated in multiple types of solid tumors, exhibiting enhanced aerobic glycolysis [10,11]. In addition to its basic role in glycolysis, HK2 also affects many important cellular processes including cellular growth and survival by direct molecular-molecular or functional interactions with the Akt/mTOR pathways [12]. Excitingly, the differences in expression level of HK2 between cancer cells and normal cells may indicate huge potential for inhibiting HK2 as therapeutic strategies to preferentially kill cancer cells.
Applications of bio-predictive dissolution tools for the development of solid oral dosage forms: current industry experience
Published in Drug Development and Industrial Pharmacy, 2022
Based on the FaCS theory, Do, Pn and Dn can be quantitatively calculated for the estimation of the rate-limiting step to inform the selection of in vitro tool. However, one major limitation of FaCS theory is that it does not take supersaturation into consideration. For instance, in vivo supersaturation is expected when dissolved weakly basic compounds are emptied from the stomach into the small intestine. Another well-known scenario is to achieve the supersaturation through enabling formulation approaches, where the functional excipients (polymers, surfactants, etc.) are employed to prevent the precipitation of the poorly soluble drug (salts, cocrystals, the amorphous or metastable form) in a highly supersaturated state. This stabilized supersaturation can render significantly higher intraluminal concentrations of the drug than the equilibrium solubility [127].
Glycometabolic rearrangements–aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
The GLUT family consists of 14 members [47], of which GLUT1-4 paly the main role in glucose transport. GLUT1 expression has been reported to correlate with histological grade or tumor size of PDAC [48], and patients with low GLUT1 expression suffer worse prognosis and unsatisfactory therapeutic response to neoadjuvant chemoradiotherapy [49]. The role of GLUT1 in PDAC is mainly to stimulate glucose uptake, thereby promoting the aerobic glycolysis and tumor progression [44].HKs are involved in the first and rate-limiting step of glycolysis to convert glucose to glucose-6-phosphate. In PDAC, HKs expression is associated with enhanced aerobic glycolysis and poor prognosis. As mentioned above, Kras is involved in the expression of HKs, which has two gene products (KRAS4A and KRAS4B) through using an alternative fourth exon. KRAS4A is the unique palmitoylation-depalmitoylation cycle of the RAS isoform, which colocalizes with HK1 on the outer membrane of the mitochondrial membrane. And based on its direct GTP-dependent interaction with HK1, it can alter the kinase activity and promote aerobic glycolysis and tumor progression [13,50]. In addition, HK2 is observed to bind to the mitochondrial membrane through voltage-dependent anion channels, which enhances glycolytic capacity of tumor cell and inhibits its apoptosis [51,52].