Formation of a disulfide bond through oxidation of cysteine residues. As shown in Scheme 80, L-aspartic acid peptide can isomerize to L-iso -aspartic acid peptide via its L-cyclic imide. Protein degradation pathways. Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways 5.1.1.1. The first pathway, which was issued in a Notice of Proposed Rulemaking (NPRM), would authorize states and other non-federal government entities, such as tribal or territorial entities, to implement time-limited importation programs, known as Section 804 Implementation Programs or SIPs, for importation of prescription drugs from Canada only. In bacteria, cocaine breakdown is initiated by cocaine esterase, which creates ecgonine methyl ester and benzoate. chemical degradation; Determination of the intrinsic stability of a drug substance molecule. products may also participate further in disulfide exchange reactions, resulting in formation of new cross-linkages. Examples of these oxidative pathways are shown in MetaCyc pathways gallate degradation II, methylgallate degradation, protocatechuate degradation I (meta-cleavage pathway), protocatechuate degradation II (ortho-cleavage pathway), and superpathway of aromatic compound degradation via 3-oxoadipate. The latter two categories of drug degradation will be discussed in Chapters 5 and 6, respectively. Degradation Pathways and Mechanisms 262 9.3 Design and Selection of a Drug Candidate Considering Drug Degradation Pathways and Mechanisms 263 9.4 Implication of the Udenfriend Reaction and Avoidance of a Formulation Design that may Fall into the "Udenfriend Trap" 265 9.5 Control of Oxygen Content in Drug Products 267 Regulation of protein degradation is required to ensure proper signaling and growth in all cells. However, they sometimes undergo chemical, physical and microbiological degradation resulting in therapeutic failure, toxicity, or loss of aesthetics. While some of the above classifications … Exp Mol Med 52, 15–30 (2020). Understanding the degradation pathways in order to achieve First to know the degradation paths to attain the stability of both drug substance and drug products. In December 2019, the Administration outlined two pathways for the importation of prescription drugs. Following storage of a secretin solution, aspartoyl3 secretin (cyclic imide) and P-aspar-tyl3 secretin (isomer) were detected in the solution by reversed-phase HPLC, indicating that isomerization occurred via the cyclic imide.794 795 An Asp-hexapeptide also exhibited isomerization via cyclic imide formation at pH values above 4.796 The rate of formation of the cyclic imide was affected by the size of the amino acid on the C-terminal side of the aspartic acid residue.797 A cyclic imide was also detected as a major degradation product of basic fibroblast growth factor at pH 5.798, Racemization has also been observed with many peptides and proteins. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency–associated liver disease. Bacterial steroid degradation has been studied mainly with Rhodococcus equi (Nocardia restrictus) and Comamonas testosteroni as representative steroid degradation bacteria for more than 50 years. Currently, several databases have included drug pathways, such as DrugBank ( 2 , 3 ), KEGG ( 4 , 5 ) and SMPDB ( … The only differences between one drug and another are the number and type of functional groups present, and the connectivity between these groups. There are also suggestions that the initial pyridine degradation may proceed without a reduction step when pyridine is first hydroxylated by Rhodococcus opacus and Arthrobacter sp. The study provides novel and primary knowledge of the stability characteristics of venetoclax under stress conditions. The drug metabolism process occurring in organs other than the Figure 1. 200, the main degradation pathway of decapeptide (an antagonist of LH-RH) above PH 7 was epimerization.802, Hydrolysis is a pathway often observed during peptide and protein degradation. These drug as metabolized by the hepatic system of body. Various Types and Mechanisms of Degradation Reactions This chapter covers most commonly occurred drug degradation reactions, except for hydrolysis, oxidation, degradation caused by interaction with excipients, and photochemical degradation. water from liquid preparation will cause the drug. Journal Biomedical and Biopharmaceutical Research, Case studies of microbial contamination in biologic product manufacturing, IN VITRO DISSOLUTION PROFILE OF SOME BRANDS OF GLIBENCLAMIDE TABLET MARKETED IN JOS METROPOLIS, Some microbiological aspects of pharmaceutical dosage forms, Advice on Degradation Products in Pharmaceuticals: A Toxicological Evaluation. Reasons for carrying out forced degradation studies include: development and validation of stability-indicating methodology, determination of degradation pathways of drug substances and drug products, discernment of degradation products in formulations that are related to drug substances versus those that are related to non–drug substances (e.g., excipients) [17,22]. • Drugs with functional groups such as esters, amides, lactones or lactams may be susceptible to hydrolytic degradation. metabisulfite hinders the photodegradation, retinol, riboflavin, furosemide and phenothiazines are very labile, R-thalidomide causes birth defect while the S-thalidomide, resonance with neighbouring functional groups. One drug causes an increase, or decrease in the CYP450 enzyme activity. Apparent rate constant (h - 1 ) at pH 9.6, 37°C and glycine buffer concentration of: degradation product.789 Similar direct deamidation of the model Asn-hexapeptide resulted in 100% formation of the aspartic acid peptide.790 791, Insulin has two asparagine residues that undergo deamidation. Pharmaceutical dosage forms are meant to maintain their physical, chemical, therapeutic, microbiological and toxicological stability in their specifications within the stated shelf-life. This pathway was contributed by Cynthia Zook, University of Minnesota, and completed by Jingfeng Feng, University of Minnesota.. 1,1,1-Trichloro-2,2-bis-(4'-chlorophenyl)ethane (DDT), the first of the chlorinated organic insecticides, is a widely distributed and persistent xenobiotic contaminant in the environment. Therefore, isomeric drugs wide pathways involved in there metabolic degradation. We proposed main degradation pathways of venetoclax under stress conditions. are Penicillins, cephalosporins, benzodiazepines. The in silico predictions indicated that these substances … Also, normal disulfide bonds in peptide and protein molecules can undergo thiol-catalyzed intra-and intermolecular exchange reactions, leading to changes in secondary and tertiary structures (Scheme 83). Oxidation of methionine residues has been observed during storage of parathyroid hormone819 and relaxin.820 Degradation of freeze-dried ribonuclease A was ascribed to oxidation because molecular oxygen was involved in the degradation process.821, Oxidation of methionine to methionine sulfoxide in small peptides was catalyzed by Fe3+ and promoted by ascorbic acid. For example, cells limit DNA replication to specific phases of growth by rapidly degrading proteins that trigger transitions between these phases. This knowledge is used primarily to develop stability-indicating analytical methods but is also useful for other purposes such as formulation development, packaging development and the design of the official stability studies. The main degradation pathways proposed were hydroxylation, hydrogen abstraction, demethylation, NO2 elimination, cleavage, and aromatic ring opening. Hydrolysis and oxidation are the two principal degradation pathways for most drugs. The vast majority of drugs are organic molecular entities. The deamidation rate was higher for asparagine residues having a smaller amino acid at the C-terminal side ofthe residue, as shown in Table 14, indicating that steric factors may influence cyclic imide formation.790 791, Deamidation of ACTH under acidic pH conditions is considered to be direct deamidation to the aspartic acid peptide since the wo-aspartic acid peptide was not observed as a. Study of Degradation Products and Degradation Pathways of ECD and Its Drug Product, ECD Kit. Lyophilized porcine pancreatic elastase exhibited denaturation during storage at 40°C and 75% relative humidity in which oxidation of tryptophyl groups was probably involved.823 Reducing sugar impurities in mannitol used as an excipient824 induced solid-state oxidative degradation of a cyclic heptapeptide. As with other articles in the series (see Animal Experiments in Addiction Science), we provide illustrative references from articles published in NIDA Notes. The covalent linkages in the aggregates of freeze-dried ribonuclease A appeared to result from the participation of lysine, asparagine, and glutamine residues as suggested by amino acid analysis of the aggregates.812813 Lyophylized formulations of recombinant tumor necrosis factor-a formed dimers and oligomers that were nonreducible.814 Upon storage, insulin formulations yielded covalent dimers; the extent of dimerization was highly dependent on the formulation.815 The deamidated A-21 asparagine of one insulin molecule and the B-1 phenylalanine residue of another were found to be involved in the formation of the dimeric species.816 The aggregates of basic fibroblast growth factor have been characterized by a systematic approach using UV spectroscopy, size-exclusion HPLC, and reversed-phase chromatography.817, Formation of disulfide bonds from cysteine residues is an oxidation reaction. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. As shown in Scheme 81, aspartic acid residues in particular are susceptible to hydrolysis in the acidic pH range. HCCHjSH —> HCCHsSSCHjCH Scheme 82. The main one was based on the initial hydroxylation of the phenylacetic acid moiety in the C-4 position and subsequent formation of a quinone imine derivative that was the starting point for further multistep degradation involving hydroxylation, decarboxylation, and oxidation reactions. By Kung-Tien Liu, Yu-Yung Lin, Yi-Chih Hsia, Jian-Hua Zhao, Chang-Yung Su, Shang-Yu Shen, Lee-Chung Men and Lie-Hang Shen. This is seen clinically in the different reactions people have to drugs, or especially when multiple drugs are co-administered. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. Cathleen Melendez, Cathleen Melendez 1. Secretin, apart from undergoing isomerization, also undergoes degradation by hydrolysis of its aspartic acid residues at position-3 and position-15.794795 Hydrolysis of aspartic acid residues under acidic conditions has also been observed with recombinant human macrophage colony-stimulating factor,803 recombinant human interleukin- 1 1 ,804 and a hexapeptide.796 Hydrolysis may also occur at serine and histidine residues.799-802, 5.1.1.4. Sci. The L-cyclic imide intermediate is capable of undergoing racemization to the D-cyclic imide and thus forms the D-aspartic acid peptide and the D-iso-aspartic acid peptide on hydrolysis. This article focuses on the different types of pharmaceutical product stability, such as chemical degradation, physical degradation, and microbial degradation. As a pharmaceutical scientist working in analytical development and drug metabolism, I found this book a great reference book, containing valuable information to gain knowledge on drug degradation and to have a better … There are many factors that can affect the stability of a pharmaceutical product. Determination of degradation pathways of drug method conditions. Intramolecular catalysis by a histidine residue was involved in this oxidation, and its effect was maximal when the histidine and methionine residues were separated by one residue.822. • It is probably the most commonly encountered mode of drug degradation because of the prevalence of such groups in medicinal agents and the ubiquitous nature of water. Deamidation of an asparagine residue to the corresponding aspartic acid residue may also occur via a mechanism that does not involve cyclic imide formation, as shown in Scheme 80. Degradation products are impurities resulting from chemical changes that occur during drug manufacturing. However, they do sometimes undergo chemical, physical and Microbiological degradation that results in therapeutic failure, toxicity, or loss of esthetic of the dosage form. Discernment of degradation products in formulations that are related to drug substances versus those that are related to non–drug substances (e.g., excipients). … Moreover some drugs are ionised by gastric pH and do not absorb very well (i.e. Forced degradation is a degradation of Degradation product , new drug substance and drug product at conditions more severe than accelerated Forced degradation, conditions. Biotransformation is the chemical modification (or modifications) made by an organism on a chemical compound. Pharmaceutical dosage forms are expected to maintain their chemical, physical, microbial, therapeutic, and toxicological stability through their shelf life. Structure elucidation of degradation products. The presence, Join ResearchGate to discover and stay up-to-date with the latest research from leading experts in, Access scientific knowledge from anywhere. Peptides and proteins having an aspartic acid residue undergo hydrolysis, isomerization, and racemization via cyclic imide formation. Other thermolytic degradation pathways include ester/amide formation, rearrangement, isomerization/epimerization, cyclization, decarboxylation, hydration/dehydration, dimerization/polymerization, etc. A draft guidance document suggests that results of one- time forced degradation studies should be included in Phase 3 INDs (Investigational New Drugs). Both pathways are proposed to proceed through a ring reduction step before the ring opening (Fig. 802 with permission.). Drugs completely inactivated during the first-pass through these organs must be given parenterally, similarly to poorly absorbed drugs. Home > Books > Wide Spectra of Quality Control. The drug metabolism happening in the liver is termed as hepatic metabolism. One chapter that should be given special attention is Chapter 3, Oxidative Degradation. Excipient Compatibility. This is because the stomach has a smaller surface area, and the drug usually does not spend very long in there (see the section on gastric motility). This is a multistep process. 7(5), 2015, 238-241 using related substances method conditions. Researchers emplo… The third generation of ADCs is designed to have a wider therapeutic window. Oxidative degradation is one of the most common degradation pathways but perhaps the most complex one. The second N enters via aspartate to form arginosuccinate, which is then cleaved into … From a pharmacogenomics perspective, the most well studied drug in this class is the thiazide diuretic hydrochlorothiazide (HCT). Chemical Degradation Last Updated on Fri, 04 Sep 2020 | Stability of Drugs The major known chemical degradation pathways for peptides and proteins are deami-dation, racemization, isomerization, hydrolysis, disulfide formation/exchange, P-elimina-tion, and oxidation. To the best of our knowledge, no structures of degradation products of venetoclax have been previously published. These include the stability of the active drug(s), interactions between, Lay abstract: Ecgonine methyl esterase cleaves ecgonine methyl ester into ecgonine and methanol. Improper degradation of DNA replication factors results in pathological conditions like cancer. This article discusses elements of a microbial control strategy, recent cases of microbial contamination in specified biologic products, the need to perform risk assessments on a periodic basis, and additional areas of improvement in the management of risks. to drug degradation 2. pH: • Acidic and alkaline pH influence the rate of decomposition of most drugs. P-galactosidase also exhibited aggregation via disulfide bond formation at relatively low water content. Structure elucidation of degradation products. Adrenocorticotropic hormone (ACTH), which has 38 amino acid residues, exhibited pseudo-first-order deamidation in the neutral-to-alkaline pH region. Most drugs are small organic molecules. microbial degradation; DOI: 10.5772/19764 . stability indicating, the stressed samples should be analyzed 238 Trivikram Rawat et al /J. … Determination of degradation pathways of drug substances and drug products. Most of the serious drug interactions are due to the interference of the metabolic clearance of one drug by another drug. 1A and D). Predict the stability of drugs and chemicals under specified conditions; Provide project management services on the design, planning and execution of experimental studies to identify the degradation products of drug and chemical substances and elucidate reaction pathways Keywords: excipient, drug -to-excipient ratio, moisture, micro environmental p H of the drug excipient mixture, temperature, and light, on dosage form stability could be the possible factors for the drug degradation process and the form a-tion of the reaction products. A FORCED DEGRADATION STUDY LIFE SCIENCE I TECHNICAL BULLETIN ISSUE N°31 / JANUARY 2011 The stability of a drug product or a drug substance is a critical parameter which may affect purity, potency and safety. (Reproduced from Ref. Fumarylacetoacetate is hydrolyzed to fumarate and acetoacetate by the enzyme fumarylacetoacetate hydrolase which is encoded by the FAH gene located on chromosome 15q25.1 and is composed of 15 exons that generate a 419 amino acid protein. Venetoclax is currently the only BCL-2 protein inhibitor on the market. Table 13. The Ubiquitin-Proteasome System (UPS) involves the targeting of polyubiquitination proteins for recognition and processing by the 26S proteasome, a multicatalytic enzyme complex that degrades the proteins, and recycles ubiquitin. By Kung-Tien Liu, Yu-Yung Lin, Yi-Chih Hsia, Jian-Hua Zhao, Chang-Yung Su, Shang-Yu Shen, Lee-Chung Men and Lie-Hang Shen. Submitted: November 4th 2010 Reviewed: April 21st 2011 Published: November 9th 2011. Microbial contaminations have a huge impact on biologic product manufacture as they introduce product variability and can cause loss of potency due to degradation or modification of product by microbial enzymes, changes in impurity profiles, and an increase in the levels of bacterial endotoxins. In addition, chemical or environmental shocks … The primary purpose was to obtain materials for steroid drugs, but recent studies showed that many genera of bacteria (Mycobacterium, Rhodococcus, Pseudomonas, etc.) : Drugs absorb water from the atmosphere causing physical, micro-organisms can render the product harmful, Once opened, a product degrades microbiologically shortening the shelf. Integrated Micro … The main degradation products formed were analyzed by LC-UV and LC-ESI-MS methods and structures were proposed. Lysosome-dependent degradation pathways: an overview Lysosomes are single-membrane-bound vesicles with an acidic lumen containing different types of hydrolases that serve for the degradation of specific substrates, of both self and non-self-origin (De Duve 2005; De Duve 1963). Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. 4. they are less lipid soluble in that state). Continue reading here: Physical Degradation, Degradation of Peptide and Protein Pharmaceuticals, Degradation Of The Drug May Make The Product Esthetically Unacceptable, Methods for Detecting Chemical and Physical Degradation, Factors Affecting the Degradation of Peptide and Protein Drugs, Natural Antioxidants in Foods and Medicinal Plants. We report the doping of TiO 2 with fluorine (F) and palladium (Pd) to synthesize F-Pd co-doped TiO 2 nanocomposites via a microwave-assisted hydrothermal synthesis method as a smart pathway to achieve efficient photocatalytic degradation of sulfamethoxazole (SMX) using both a solar simulator and direct sunlight irradiation. In such cases, called first-order elimination (or kinetics), the metabolism rate of the drug is a constant fraction of the drug remaining in the body (ie, the drug has a specific half-life). Drug metabolism is normally divided into two phases, phase I (or functionalisation reactions) and phase II (or conjugative reactions). sodium, carbenicillin free acid, ticarcillin sodium, microbial recovery: Pharmaceutical dosage forms. The intrinsic stability of a water molecule from the cells and their components recycled key degradation pathways the. By room or sunlight integrated Micro … the lysosomal and the ubiquitin-mediated work... 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