More generally, xenobiotic metabolism (from the Greek xenos “stranger” and biotic “related to living beings”) is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism’s normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). In summary, genome editing based on CRISPR/Cas9 has been identified as a breakthrough technology in constructing animal models. Novel animal models are not only conducive to the basic research of human diseases, but also can be used to study the molecular mechanisms of drug pharmacodynamics, toxicity and clinical use. Furthermore, DMPK animal models will promote the study of DMPK mechanisms and strengthen the relationship between drug metabolism and pharmacology/toxicology.
- A hint of the presence of active metabolites may come from a lack of PK–PD correlation or a lack of in vivo efficacy–in vitro potency correlation of a drug molecule.
- The role of renal and intestinal enzymes in herbal product metabolism has been uncovered.
- Another reported substrate of POR is an aldehyde intermediate (M-CHO) that is formed during the metabolism of imrecoxib, which is a moderate COX-2 inhibitor325.
- These results suggest that FXR may be developed as a therapeutic target for cholesterol gallstone disease.
There is definitive evidence for CYP2B6 and 3A5 expression in human kidney, while multiple CYPs are expressed in intestine27,28. The role of renal and intestinal enzymes in herbal product metabolism has been uncovered. Aminoglycoside antibiotics are leading causes for nephrotoxicity; combination with herbs or dietary supplements at reduced dosage is possible to reduce the risk of drug-mediated renal toxicity. A recent study the 10 strongest vodkas in the world ark behavioral health revealed that moringa oleifera seed oil could limit gentamicin-induced oxidative nephrotoxicity29. Additional herbs have been identified as having effects on intestinal metabolism, such as the extracts of Yin-Chen-Hao Tang (YCHT), a very popular hepatoprotective three-herb formula in China and Japan30. These findings contribute to the understanding of the metabolic characteristics of renal and intestinal metabolism.
An accumulation of strong research evidence indicates that disease–drug and drug–disease interactions can have a profound effect on the response to a medication, yet most of the existing results are only from animal models. In recent years PBPK modeling has gradually been applied to the prediction of disease–drug interactions188,57. However, further clinical study or real-life experience is needed to justify results from PBPK modeling. Additionally, the potential mechanism of disease–drug interactions remains poorly characterized. Therefore, further studies are also needed to reveal the in-depth and comprehensive mechanism involved in disease–drug interactions.
For example, rapid metabolizers clear the drug very quickly, and the therapeutic concentration of the drug in the blood and tissues may not be reached. In other patients, the drug is metabolized so slowly that it accumulates in the blood stream. The higher concentration of the drug in the body creates a greater potential alcohol as a seizure trigger for adverse effects. Oxidative pathways, including sp3-hybridized C-hydroxylation, unsaturated C-oxidation, N-dealkylation/deamination, O-dealkylation, S-dealkylation, N-oxidation, S-oxidation, and oxidative cleavage of esters and amides classified by functional groups are the most common biotransformations.
In vitro metabolism studies identified a quinone metabolite 41 and a hydroquinone metabolite 43 which might be formed from reduction of the reactive para-quinone metabolite 42. Subsequent in vitro trapping studies identified a bis-cyano adduct 45, indicating the formation of reactive iminium ion species 4448. These results suggest that compound 40 is subject to bioactivation through pathways involving at least reactive quinone species 41 and 42 and iminium species 44 (Scheme 3). Subsequently, (2S,3R)-(+)-3-(3-hydroxyphenyl)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol (46,Scheme 4) was synthesized in the effort to minimize formation of reactive metabolites48.
Clinical Significance
For example, losartan (27, Fig. 4) is used as an angiotensin II receptor antagonist for treatment of hypertension in human. The alcohol functional group of losartan is oxidized to the carboxylic acid group to afford the metabolite EXP3174 (28, Fig. 4) in the body27. In vitro studies showed that EXP3174 has an IC50 of 0.2 nmol/L against the angiotensin II receptor, compared to 4 nmol/L for losartan. Heart failure (HF) is considered an epidemic disease in the modern world affecting approximately 1%–2% of the adult population. Many CYP enzymes have been identified in the heart and their levels have been reported to be altered during HF. There is a great deal of discrepancy between various reports on CYP alterations during HF, likely due to differences in disease severity, the species in question and other underlying conditions.
Animal models are mainly used in experimental physiology, experimental pathology and experimental therapeutics, especially in the study of new drugs. In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human PK and toxicokinetics250. However, with the development of gene editing technology, animal models of special ADME genes are needed to better study the mechanisms of DMPK, including the metabolic pathway and its regulatory mechanism. An accumulation of strong research evidence indicates that disease–drug and drug–disease interactions can have a profound effect on the response to a medication, but most of the existing results are only from animal models.
4. Trends in microbiota mediated drug–drug interactions
An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively. Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.[8] This example of a biomimetic reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical trimebutine, desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug.
Furthermore, the DDIs between JBP485 and entecavir through the competitive inhibition of OAT1 and OAT3 significantly decreased the renal excretion of both compounds96. Probenecid, by inhibiting OAT1 and OAT3, reduced the accumulation of cephaloridine and subsequently nephrotoxicity97,98. Most drugs are mainly cleared from the body through metabolizing enzyme-mediated processes34. Some metabolizing enzymes (e.g., CYP2D6, 2C9 and 2C19, etc.) are polymorphic in nature and exist in two or more variant forms with different enzymatic activity in different individuals. Poor metabolizers (individuals with low or no enzymatic activity) could have much higher drug exposure than extensive metabolizers (individuals with high enzymatic activity) when a given dose of a drug is administered.
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Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. Phase II reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions; thus, phase numbers reflect functional rather than sequential classification. Secondary metabolites are compounds produced by an organism that are not required for primary metabolic processes, although they can have important ecologic and other functions.
They often produce not just one member of a metabolite class, but a complex mixture of analogues (i.e. metabolites with closely related chemical structures). Precise definition of small molecules is hindered by the fact that they rapidly lose any resemblance to the parent structure. Metabolite can also represent a building block of a larger structure or a degraded product destined for excretion. Primary metabolites are synthesized by the cell because they are indispensable for their growth. Significant representatives are amino acids, alcohols, vitamins (B2 and B12), polyols, organic acids, as well as nucleotides (e.g. inosine-5′-monophosphate and guanosine-5′-monophosphate).
The basic mechanism and rules of drug metabolism cannot be characterized based on the structures of the drugs alone, because the presence of metabolic intermediates that would allow for the intra-molecular rearrangement are likely factors in unusual metabolite formation. This subtle but potentially significant hypothesis suggests that the electron or radical-mediated modulation of biotransformation characteristics may represent uncommon underlying mechanisms for undesirable metabolic pathways, with relevant toxicological consequences. Drug metabolism or drug biotransformation is the process by which xenobiotics are enzymatically modified to make them more readily excretable and eliminate pharmacological activity. Understanding the metabolic fate and the corresponding enzymes are important with regard to metabolite toxicity and drug–drug interaction risks.
Novel role for metabolites in cellular metabolism discovered
The majority of in vivo biotransformations are oxidation, while reductive reactions preferentially occur in anaerobic or low-O conditions. A considerable number of the same enzymes that catalyze oxidative metabolism, such as P450s, aldo-keto reductase, carbonyl reductase, xanthine oxidase, aldehyde oxidase, and quinone oxidoreductase, can also be involved in reductions. Under the catalysis of some specific enzymes or the involvement of reducing agents, some uncommon reductive metabolic pathways are observed. On the other hand, early and appropriate antimicrobial treatment is the predominant intervening measure to decrease patient mortality227.
The metabolism of drugs can occur in various reactions, categorized as phase I (modification), phase II (conjugation), and in some instances, phase III (additional modification and excretion). In biochemistry, a metabolite is an intermediate or end product of metabolism.[1]The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, catalytic activity of their own (usually as a cofactor to an enzyme), defense, and interactions with other organisms (e.g. pigments, odorants, and pheromones). Generally, conjugation pathways involve the addition of an endogenous hydrophilic group to a drug or its metabolite(s), including glucuronidation, sulfation, glutathione conjugation, amino acid conjugation, acetylation, and methylation.
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