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35-471: Common side effects include nausea , vomiting , loss of appetite , and skin rashes . It is a sulfonamide and bacteriostatic . It resembles a component of folic acid . It prevents folic acid synthesis in the bacteria that must synthesize their own folic acid. Mammalian cells, and some bacteria, do not synthesize but require preformed folic acid (vitamin B9); they are therefore insensitive to sulfamethoxazole. It

70-904: A limited number of human studies implicate these epoxides in reducing hypertension ; protecting against myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation ; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase ). In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of another product of CYP450 enzymes (e.g. CYP4A1 , CYP4A11 , CYP4F2 , CYP4F3A , and CYP4F3B ) viz., 20-Hydroxyeicosatetraenoic acid (20-HETE), principally in

105-556: A missense variant in exon 2 (NM_000771.3:c.269T>C, p. Leu90Pro, rs72558187). CYP2C9*13 prevalence is approximately 1% in the Asian population, but in Caucasians this variant prevalence is almost zero. This variant is caused by a T269C mutation in the CYP2C9 gene which in turn results in the substitution of leucine at position-90 with proline (L90P) at the product enzyme protein. This residue

140-541: A result, the metabolic ratio – the ratio of unchanged drug to metabolite – is higher in PMs. A study of the ability to metabolize warfarin among the carriers of the most well-characterized CYP2C9 genotypes (*1, *2 and *3), expressed as a percentage of the mean dose in patients with wild-type alleles (*1/*1), concluded that the mean warfarin maintenance dose was 92% in *1/*2, 74% in *1/*3, 63% in *2/*3, 61% in *2/*2 and 34% in 3/*3. CYP2C9*3 reflects an Ile 359- Leu (I359L) change in

175-738: A study published in 2014, the AT genotype showed slightly higher expression than TT, but both much higher than AA. Another variant, rs1934969 (in studies of 2012 and 2014) have been shown to affect the ability to metabolize losartan: carriers of the TT genotype have increased CYP2C9 hydroxylation capacity for losartan comparing to AA genotype, and, as a result, the lower metabolic ratio of losartan, i.e., faster losartan metabolism. Most inhibitors of CYP2C9 are competitive inhibitors . Noncompetitive inhibitors of CYP2C9 include nifedipine , phenethyl isothiocyanate , medroxyprogesterone acetate and 6-hydroxyflavone . It

210-437: Is a structural analog of para -aminobenzoic acid (PABA). They compete with PABA to bind to dihydropteroate synthetase and inhibit conversion of PABA and dihydropteroate diphosphate to dihydrofolic acid, or dihydrofolate. Inhibiting the production of dihydrofolate intermediate interferes with the normal bacterial synthesis of folic acid (folate). Folate is an essential metabolite for bacterial growth and replication because it

245-453: Is an enzyme protein . The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene . The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme. CYP2C9 is a crucial cytochrome P450 enzyme, which plays a significant role in

280-605: Is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant. Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label. The two most well-characterized variant alleles are CYP2C9*2 (NM_000771.3:c.430C>T, p.Arg144Cys, rs1799853) and CYP2C9*3 (NM_000771.3:c.1075A>C, p. Ile359Leu, rs1057910), causing reductions in enzyme activity of 30% and 80%, respectively. On

315-481: Is associated with a decreased dose of warfarin as compared to the allele G (77% global frequency). Another variant, rs4917639, according to a 2009 study, has a strong effect on warfarin sensitivity, almost the same as if CYP2C9*2 and CYP2C9*3 were combined into a single allele. The C allele at rs4917639 has 19% global frequency. Patients with the CC or CA genotype may require decreased dose of warfarin as compared to patients with

350-493: Is by far the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega-3 fatty acids. CYP2C9 may also metabolize linoleic acid to the potentially very toxic products, coronaric acid (also termed leukotoxin) and vernolic acid (also termed isoleukotoxin); these linoleic acid epoxides cause multiple organ failure and acute respiratory distress in animal models and may contribute to these syndromes in humans. The CYP2C9 gene

385-713: Is highly polymorphic. At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses. Information about how human genetic variation of CYP2C9 affects response to medications can be found in databases such PharmGKB, Clinical Pharmacogenetics Implementation Consortium (CPIC). The label CYP2C9*1

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420-591: Is metabolized in the human liver to at least 5 metabolites. These metabolites are the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The CYP2C9 enzyme is responsible for the formation of the N4-hydroxy metabolite. In vitro studies suggest sulfamethoxazole is not a substrate of the P-glycoprotein transporter. Excretion Sulfamethoxazole

455-527: Is near the access point for substrates and the L90P mutation causes lower affinity and hence slower metabolism of several drugs that are metabolized CYP2C9 by such as diclofenac and flurbiprofen . However, this variant is not included in the tier 1 recommendations of the PGx Working Group because of its very low multiethnic minor allele frequency and a lack of currently available reference materials. As of 2020

490-522: Is primarily renally excreted via glomerular filtration and tubular secretion. About 20% of the sulfamethoxazole in urine is the unchanged drug, about 15–20% is the N-glucuronide conjugate, and about 50–70 % is the acetylated metabolite. Sulfamethoxazole is also excreted in human milk. Side effects In medicine , a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that

525-520: Is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used for a specific effect may be used specifically because of a beneficial side-effect; this is termed " off-label use " until such use is approved. For instance, X-rays have long been used as an imaging technique ; the discovery of their oncolytic capability led to their use in radiotherapy for ablation of malignant tumours . The World Health Organization and other health organisations characterise

560-474: Is used in DNA synthesis , primarily at thymidylate and purine biosynthesis, and amino acids synthesis, including serine, glycine and methionine. Hence, blockage of folate production inhibits the folate-dependent metabolic processes for bacterial growth. Since it inhibits bacterial growth, sulfamethoxazole is considered a bacteriostatic antibiotic. Sulfonamides are selective against bacteria because they interfere with

595-471: The amino acid sequence, and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin. Its prevalence varies with race as: The Association for Molecular Pathology Pharmacogenomics (PGx) Working Group in 2019 has recommended a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) to be included in assays for CYP2C9 testing. CYP2C9 variant alleles recommended as Tier 1 by

630-518: The EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis , endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems. Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans, and in humans

665-403: The PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. This recommendation was based on their well-established functional effects on CYP2C9 activity and drug response availability of reference materials, and their appreciable allele frequencies in major ethnic groups. The following CYP2C9 alleles are recommended for inclusion in tier 2: CYP2C9*12, *13, and *15. CYP2C9*13 is defined by

700-431: The areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid , epoxyeicosatetraenoic acid , and epoxydocosapentaenoic acid sections on activities and clinical significance). Such studies also indicate that the eicosapentaenoic acids and EEQs are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or equal in potency to

735-573: The basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. The carriers of homozygous CYP2C9*1 variant, i.e. of the *1/*1 genotype, are designated extensive metabolizers (EM), or normal metabolizers. The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. just one of these alleles (*1/*2, *1/*3) are designated intermediate metabolizers (IM), and those carrying two of these alleles, i.e. homozygous (*2/*3, *2/*2 or *3/*3) – poor metabolizers (PM). As

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770-805: The drug, without assuming that they were necessarily caused by the drug. Both healthcare providers and lay people misinterpret the frequency of side effects as describing the increase in frequency caused by the drug. Most drugs and procedures have a multitude of reported adverse side effects; the information leaflets provided with virtually all drugs list possible side effects. Beneficial side effects are less common; some examples, in many cases of side-effects that ultimately gained regulatory approval as intended effects, are: CYP2C9 1OG2 , 1OG5 , 1R9O , 4NZ2 1559 72303 ENSG00000138109 ENSMUSG00000067231 P11712 n/a NM_000771 NM_028191 NP_000762 n/a Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9 )

805-443: The entire Gel-Coombs spectrum of hyperactivity reactions. Type 1 reactions include immunoglobulin E (IgE)-mediated reactions such as urticaria, angioedema, and anaphylaxis. In contrast, non-type 1 hypersensitivities are believed to be caused by metabolites of sulfonamides. Therefore, the liver and kidney are the determining factors of these other hypersensitivity reactions; alterations in kidney or liver functions may increase or decrease

840-495: The evidence level for CYP2C9*13 in the PharmVar database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive. Not all clinically significant genetic variant alleles have been registered by PharmVar . For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Allele A (23% global frequency)

875-412: The frequencies of these reactions. One study has shown the allergic reaction rate to be about 3.0% over 359 courses of therapy. Of the allergic reactions, skin rashes, eosinophilia and drug fever were the most common, while serious reactions were less common. Sulfamethoxazole is contraindicated in people with a known hypersensitivity to trimethoprim or sulfonamides. Sulfamethoxazole, a sulfanilamide ,

910-546: The heart, the growth of various cancers, inflammation , blood vessel formation, and pain perception; limited studies suggest but have not proven that these epoxides may function similarly in humans (see Epoxyeicosatrienoic acid and Epoxygenase ). Since the consumption of omega-3 fatty acid -rich diets dramatically raises the serum and tissue levels of the EDP and EEQ metabolites of the omega-3 fatty acid, i.e. docosahexaenoic and eicosapentaenoic acids, in animals and humans and in humans

945-982: The known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids , converting these fatty acids to a wide range of biologically active products. In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide (EETs) stereoisomer sets: 5 R ,6 S -epoxy-8Z,11Z,14Z-eicosatetraenoic and 5 S ,6 R -epoxy-8Z,11Z,14Z-eicosatetraenoic acids; 11 R ,12 S -epoxy-8Z,11Z,14Z-eicosatetraenoic and 11 S ,12 R -epoxy-5Z,8Z,14Z-eicosatetraenoic acids; and 14 R ,15 S -epoxy-5Z,8Z,11Z-eicosatetraenoic and 14 S ,15 R -epoxy-5Z,8Z,11Z-eicosatetraenoic acids. It likewise metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers). Animal models and

980-540: The metabolism, by oxidation, of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. The protein is mainly expressed in the liver , duodenum , and small intestine . About 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin , and other routinely prescribed drugs such as acenocoumarol , tolbutamide , losartan , glipizide , and some nonsteroidal anti-inflammatory drugs . By contrast,

1015-512: The placenta. About 70% of the drug is bound to plasma proteins. Its Tmax (or time to reach maximum drug concentration in plasma) occurs 1 to 4 hours after oral administration. The mean serum half-life of sulfamethoxazole is 10 hours. However, the half-life of the drug noticeably increases in people with creatinine clearance rates equal to or less than 30 mL/minute. A half-life of 22–50 hours has been reported for people with creatinine clearances of less than 10 mL/minute. Metabolism Sulfamethoxazole

1050-663: The principle enzymes which metabolizes 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy-octadecenoic acids (also termed coronaric acid , linoleic acid 9,10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic acids (also termed vernolic acid , linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs). Animal model studies implicate these epoxides in regulating: hypertension , myocardial infarction and other insults to

1085-428: The probability of experiencing side effects as: The European Commission recommends that the list should contain only effects where there is "at least a reasonable possibility" that they are caused by the drug and the frequency "should represent crude incidence rates (and not differences or relative risks calculated against placebo or other comparator)". The frequency describes how often symptoms appear after taking

Sulfamethoxazole - Misplaced Pages Continue

1120-416: The synthesis of folate, a process which does not occur in humans. Humans do not synthesize folate, and must acquire it through diet. Absorption Sulfamethoxazole is well-absorbed when administered topically. It is rapidly absorbed when it is orally administered. Distribution Sulfamethoxazole distributes into most body tissues as well as into sputum, vaginal fluid, and middle ear fluid. It also crosses

1155-416: The wild-type AA genotype. Another variant, rs7089580 with T allele having 14% global frequency, is associated with increased CYP2C9 gene expression. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels compared to wild-type AA genotype. Increased gene expression due to rs7089580 T allele leads to an increased rate of warfarin metabolism and increased warfarin dose requirements. In

1190-679: Was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme. Following is a table of selected substrates , inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class. Inhibitors of CYP2C9 can be classified by their potency , such as: Strong Moderate Weak Unspecified potency Strong Weak CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. alkene ) bonds to form epoxide products that act as signaling molecules. It along with CYP2C8, CYP2C19 , CYP2J2 , and possibly CYP2S1 are

1225-937: Was introduced to the United States in 1961. It is now mostly used in combination with trimethoprim (abbreviated SMX-TMP ). The SMX-TMP combination is on the WHO Model List of Essential medicines as a first-choice treatment for urinary tract infections. Other names include: sulfamethalazole and sulfisomezole. The most common side effects of sulfamethoxazole are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria ). There have been rare instances where severe adverse reactions have resulted in fatalities. These include Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis , fulminant hepatic necrosis , agranulocytosis , aplastic anemia , and other blood dyscrasias . Allergic reactions to Sulfonamides have been shown to include

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