Is metabolite a drug?
14564960#1
An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body. Usually these effects are similar to those of the parent drug but weaker, although they can still be significant (see e.g. 11-hydroxy-THC, morphine-6-glucuronide). Certain drugs such as codeine and tramadol have metabolites (morphine and "O"-desmethyltramadol respectively) that are stronger than the parent drug and in these cases the metabolite may be responsible for much of the therapeutic action of the parent drug. Sometimes, however, metabolites may produce toxic effects and patients must be monitored carefully to ensure they do not build up in the body. This is an issue with some well-known drugs such as pethidine (meperidine) and dextropropoxyphene.
Active metabolite
14564960#0
An active metabolite is an active form of a drug after it has been processed by the body.
Active metabolite
14564960#2
Sometimes drugs are formulated in an inactive form that is designed to break down inside the body to form the active drug. These are called prodrugs. The reasons for this type of formulation may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better absorbed by the body or has superior pharmacokinetics (e.g., lisdexamphetamine).
Active metabolite
14563386#9
Like other SCARs-inducing drugs, DRESS syndrome-inducing drugs or their metabolites stimulate CD8 T or CD4 T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this stimulation involves subverting the antigen presentation pathways of the innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell (APC) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC); and presents the MHC-associated peptides to the T-cell receptor on CD8 T or CD4 T cells. Those peptides expressing a drug-related, non-self epitope on their HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR proteins may bind to a T-cell receptor to stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. Importantly, however, non-self epitopes must bind to specific HLA serotypes in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a DRESSs-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite. Thus, only rare individuals are predisposed to develop SCARs in response to a particular drug on the bases of their expression of HLA serotypes. Studies have identified several HLA serotypes associated with development of the DRESS syndrome in response to certain drugs, have developed tests to identify individuals who express some of these serotypes, and thereby have identified individuals who should avoid certain DRESS syndrome-inducing drugs.
Drug reaction with eosinophilia and systemic symptoms
16374808#17
Flumequine is considered to be well absorbed and is excreted in the urine and feces as the glucuronide conjugates of the parent drug and 7-hydroxyflumequine. It is eliminated within 168 hours post-dosing. However, studies concerning the calf liver showed additional unidentified residues, of which a new metabolite, ml, represented the major single metabolite 24 hours after the last dose and at all subsequent time points. The metabolite ml, which exhibited no antimicrobial activity, was present in both free and protein-bound fractions. The major residue found in the edible tissues of sheep, pigs, and chickens was parent drug together with minor amounts of the 7-hydroxy-metabolite. The only detected residue in trout was the parent drug.
Flumequine
826690#4
Compounds begin to break down as soon as they enter the body. The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug (see prodrug).
ADME
28649#15
Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8 T cells or CD4 T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the antigen presentation pathways of the innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell (APC) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC); and presents the MHC-associated peptides to T-cell receptors on CD8 T cells or CD4 T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms (HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR) can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. In all these cases, however, a non-self epitope must bind to a specific HLA serotype (i.e. variation) in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite. Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes: Studies have identified several HLA serotypes associated with development of SJS, SJS/TEN, or TEN in response to certain drugs. In general, these associations are restricted to the cited populations.
Stevens–Johnson syndrome
16563762#9
JWH-018 usage is readily detected in urine using "spice" screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites. JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 users of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate.
JWH-018
21354286#11
AGEP also differs from the other SCARs disorders in respect to the level of evidence supporting the underlying mechanism by which a drug or its metabolite stimulates CD8 T or CD4 T cells. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this stimulation involves subverting the antigen presentation pathways of the innate immune system. A drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell (APC) takes up these proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC) (APC); and presents the MHC-associated peptides to the T-cell receptor on CD8 T or CD4 T cells. Those peptides expressing a drug-related, non-self epitope on their HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR proteins may bind to a T-cell receptor to stimulate the receptor-bearing parent T cell to attack self tissues. Alternatively, a drug or metabolite may also stimulate T cells by inserting into the groove on a HLA protein to serve as a non-self epitope, bind outside of this groove to alter a HLA protein so that it forms a non-self epitope, or bypass the APC by binding directly to a T cell receptor. However, non-self epitopes must bind to specific HLA serotypes to stimulate T cells and the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them. Since a SCARs-inducing drug or metabolite interacts with only one or a few HLA serotypes, their ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or metabolite. Thus, only rare individuals are predisposed to develop SCARs in response to a particular drug on the bases of their expression of HLA serotypes. Studies have identified several HLA serotypes associated with development of DRESS syndrome, SJS, SJS/TEN, and TEN in response to various drugs which elici these disorders, developed tests to identify individuals who express these serotypes, and thereby determined that these individuals should avoid the offending drug. HLA serotypes associated with AGEP and specific drugs have not been identified. A study conducted in 1995 identified of HLA-B51, HLA-DR11, and HLA-DQ3 of unknown serotypes to be associated with development of AGEP but the results have not been confirmed, expanded to identify the serotypes involved, nor therefore useful in identifying individuals predisposed to develop AGEP in response to any drug. Similarly, a specific T cell receptor variant has been associated with the development of DRESS syndrome, SJS, SJS/TEN, and TEN but not AGEP.
Acute generalized exanthematous pustulosis
477493#2
Metabolites from chemical compounds, whether inherent or pharmaceutical, are formed as part of the natural biochemical process of degrading and eliminating the compounds. The rate of degradation of a compound is an important determinant of the duration and intensity of its action. Profiling metabolites of pharmaceutical compounds, drug metabolism, is an important part of drug discovery, leading to an understanding of any undesirable side effects.
Metabolite
14563386#10
A drug or its metabolite may also stimulate CD8 T or CD4 T cells to initiate autoimmune responses by directly binding to the T cell receptors on these T cells. Again, this binding appears to develop only on certain T cell receptors. Since the genes for these receptors are highly edited, i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) T cell receptors while an individual express only a fraction of these, a drug's or its metabolite's ability to induce the DRESS syndrome by interacting with a T cell receptor is limited to those individuals whose T cells express a T cell receptor(s) that can interact with drug or its metabolite. Thus, only rare individuals are predisposed to develop a SCARs disorder in response to a particular drug on the bases of their expression of specific cell receptor types. While the evidence supporting these ideas is limited, one study identified the preferential presence of the TCR-V-b and complementarity determining region 3 in T cell receptors found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T cell receptors are involved in the development of specific drug-induced SCARs.
Drug reaction with eosinophilia and systemic symptoms
1029211#10
Metabolites are the intermediates and products of metabolism. Within the context of metabolomics, a metabolite is usually defined as any molecule less than 1 kDa in size. However, there are exceptions to this depending on the sample and detection method. For example, macromolecules such as lipoproteins and albumin are reliably detected in NMR-based metabolomics studies of blood plasma. In plant-based metabolomics, it is common to refer to "primary" and "secondary" metabolites. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments. By contrast, in human-based metabolomics, it is more common to describe metabolites as being either endogenous (produced by the host organism) or exogenous. Metabolites of foreign substances such as drugs are termed xenometabolites.
Metabolomics