Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.
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PMID:In vitro forecasting of drugs that may interfere with codeine bioactivation. 142 9

Three markers of free radical oxidation of lipids--9 cis, 11 trans isomer of linoleic acid, conjugated dienes and ultraviolet fluorescence products--were measured in the phospholipid fraction of duodenal juice collected in the first 10 min after an intravenous injection of secretin. The volume of aspirate was similar in 11 controls and in 25 patients who had sustained an attack of pancreatitis 6 weeks earlier--acute pancreatitis (AP) 10, chronic pancreatitis (CP) 15. The concentration of each marker was very significantly higher in the patients; the output of the isomer gave the best discrimination from controls; and ultraviolet fluorescence products were substantially higher in the subgroup with CP than with AP. The serum % molar ratio of the isomer to linoleic acid was measured in 25 controls, 14 AP and 17 CP patients: the highest levels were found in the CP group. Heightened hepatic free radical activity involving lipid isomerization as well as lipid peroxidation pathways is a feature of pancreatitis--probably antedating the attack and persisting well after clinical recovery--the difference between CP and AP being in the degree of abnormality. We argue that these hepatic changes mirror changes in pancreatic-acinar cells and that increased free radical activity in both organs is due to a shortfall of antioxidants in the face of cytochromes P450 induction by xenobiotics. Therefore, a combination of preventive and chain-breaking antioxidants may be useful in preventing further attacks of pancreatitis and controlling background pain in chronic disease.
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PMID:Heightened free radical activity in pancreatitis. 237 63

The case history of a 10-yr old boy with calcific chronic pancreatitis is reported. His theophylline clearance of 450 ml/kg/h was several times higher than normal, indicating induction of cytochromes P450. Painful attacks disappeared concurrently with administration of antioxidants. The possible relevance of these findings is discussed in the context of chronic pancreatitis in childhood.
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PMID:Antioxidants to treat chronic pancreatitis in childhood? Case report and possible implications for pathogenesis. 336 Nov 61

Flurbiprofen is a chiral non-steroidal anti-inflammatory drug used in the treatment of pain or inflammation. The primary routes of biotransformation for (R)- and (S)-flurbiprofen are oxidation (presumably cytochrome P450) and conjugation. To date, the specific cytochrome P450 (P450) involved in the oxidative metabolism of this compound (specifically 4'-hydroxylation) has not been elucidated. Experiments were conducted to characterize the kinetic parameters (Km and Vmax) for the 4'-hydroxylation of (R)- and (S)-flurbiprofen in human liver microsomes, to determine if enantiomeric interactions occur when both enantiomers are present, and to identify the specific P450 form(s) involved in this reaction. In human liver microsomes, the Km and Vmax (mean +/- SD) for (R)-4'-hydroxy-flurbiprofen formation were 3.1 +/- 0.8 microM and 305 +/- 168 pmol.min-1.mg protein)-1, respectively. In comparison, the Km and Vmax (mean +/- SD) for (S)-4'-hydroxy-flurbiprofen formation were 1.9 +/- 0.4 microM and 343 +/- 196 pmol.min-1.mg protein-1, respectively. Enantiomeric interaction studies revealed a decrease in Km and Vmax for both enantiomers and an apparent loss of stereoselectivity. Racemic-warfarin, tolbutamide, alpha-naphthoflavone and erythromycin were studied as potential inhibitors of this process. The estimated Ki values for the inhibition of (R)- and (S)-4'-hydroxy-flurbiprofen formation by racemic-warfarin were 2.2 and 4.7 microM. This reaction was also inhibited by tolbutamide. In contrast, erythromycin and alpha-naphthoflavone had no appreciable effect on 4'-hydroxy-flurbiprofen formation. cDNA-expression of individual forms was used to determine which P450 was involved in 4'-hydroxy-flurbiprofen formation. P450 2C9 and an allelic variant (R144C) readily catalyzed the formation of 4'-hydroxy-flurbiprofen. P450 1A2 was also active albeit with a turnover rate 1/140th that of P450 2C9R144C (P450s 2C8, 2E1 and 3A4 were not active toward either enantiomer). The results of these studies indicate that the enantiomers of flurbiprofen may exhibit stereoselectivity with respect to enzyme affinity but have roughly equal maximum formation velocities. Additionally, these two enantiomers may compete for the enzyme resulting in lower maximum velocities for both enantiomers. Finally, of those P450 forms examined, only P450 2C9 and an allelic variant catalyzed the 4'-hydroxylation of both (R)- and (S)-flurbiprofen.
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PMID:Role of cytochrome P450 2C9 and an allelic variant in the 4'-hydroxylation of (R)- and (S)-flurbiprofen. 776 8

While classifications into generations according to antimicrobial activity has helped clinicians incorporate the increasing number of cephalosporins into their pharmacological repertoire, adverse effects among the different agents fail to follow similar categories. In general, cephalosporins are fairly well tolerated antibiotics, and toxicity has been limited to specific agents. Subtle differences in chemical structure and pharmacokinetics can influence the potential for adverse effects. The route of administration may result in minor adverse reactions, including thrombophlebitis and pain. The most common adverse effects of cephalosporins are allergic reactions, occurring in 0.9 to 3.2% of patients. Cephalosporins have very rarely been associated with haematological toxicity (less than 1% of patients), but specific agents have been associated with neutropenia, hypoprothrombinaemia, haemolytic anaemia, and problems with platelet production and function. Other reactions include localised gastrointestinal disturbances, hepatotoxicity (e.g. biliary sludging), nephrotoxicity and mild central nervous system effects. The cephalosporins are generally well tolerated in the paediatric population. Very few interactions have been observed between cephalosporins and other drugs, largely because cephalosporins do not affect the microsomal P450 hepatic enzyme system. While cephalosporins are considered to be relatively 'safe' drugs, the introduction of newer members warrants continued careful observation for reporting of adverse drug reactions.
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PMID:Adverse effects of newer cephalosporins. An update. 839 90

Current practice predicates the use of multiple drug combinations in the treatment of neuropathic pain. These combinations may be required because of multiple pain symptoms directly arising from neuropathic pathology, other symptoms attributable to the chronicity and severity of the patient's pain or conditions unrelated to their pain. A fear exists that combination drug use or the addition of a new drug to a therapeutic regimen may lead to increased drug toxicity or decreased efficacy. Many of the drug interactions of significance to neuropathic pain physicians involve the cytochromes P450 2D6 and 3A3/4 isoenzymes. Drug interactions should be more predictable based on the knowledge of which compounds induce, inhibit or are metabolized by specific cytochrome P450 enzymes. Mechanisms of induction or inhibition of biotransformation via the P450 hepatic enzyme system are discussed and various inducers, inhibitors and substrates relating to neuropathic pain pharmacotherapy are listed.
Pain 1997 Oct
PMID:Drug interactions in human neuropathic pain pharmacotherapy. 941 51

Capsaicin is a common dietary constituent and a popular homeopathic treatment for chronic pain. Exposure to capsaicin has been shown to cause various dose-dependent acute physiological responses including the sensation of burning and pain, respiratory depression, and death. In this study, the P450-dependent metabolism of capsaicin by recombinant P450 enzymes and hepatic and lung microsomes from various species, including humans, was determined. A combination of LC/MS, LC/MS/MS, and LC/NMR was used to identify several metabolites of capsaicin that were generated by aromatic (M5 and M7) and alkyl hydroxylation (M2 and M3), O-demethylation (M6), N- (M9) and alkyl dehydrogenation (M1 and M4), and an additional ring oxygenation of M9 (M8). Dehydrogenation of capsaicin was a novel metabolic pathway and produced unique macrocyclic, diene, and imide metabolites. Metabolism of capsaicin by microsomes was inhibited by the nonselective P450 inhibitor 1-aminobenzotriazole (1-ABT). Metabolism was catalyzed by CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Addition of GSH (2 mM) to microsomal incubations stimulated the metabolism of capsaicin and trapped several reactive electrophilic intermediates as their GSH adducts. These results suggested that reactive intermediates, which inactivated certain P450 enzymes, were produced during catalytic turnover. Comparison of the rate and types of metabolites produced from capsaicin and its analogue, nonivamide, demonstrated similar pathways in the P450-dependent metabolism of these two capsaicinoids. However, production of the dehydrogenated (M4), macrocyclic (M1), and omega-1-hydroxylated (M3) metabolites was not observed for nonivamide. These differences may be reflective of the mechanism of formation of these metabolites of capsaicin. The role of metabolism in the cytotoxicity of capsaicin and nonivamide was also assessed in cultured lung and liver cells. Lung cells were markedly more sensitive to cytotoxicity by capsaicin and nonivamide. Cytotoxicity was enhanced 5 and 40% for both compounds by 1-ABT in BEAS-2B and HepG2, respectively. These data suggested that metabolism of capsaicinoids by P450 in cells represented a detoxification mechanism (in contrast to bioactivation).
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PMID:Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. 1264 34

Prostaglandins are important modulators of pain and inflammation. Both, pain and inflammation can be inhibited either at the level of the phospholipase A2 by corticosteroids or at the level of the cyclooxygenase (COX) by non steroidal anti-inflammatory drugs (NSAIDs). Formally, "cyclooxygenase" in general was thought to be responsible for the synthesis of prostaglandins involved in pain, inflammation and fever as well as cytoprotection in the stomach, hemostasis and blood flow in the kidneys. Later, two isoenzymes, cyclooxygenase-1 and cyclooxygenase-2 were discovered. It was postulated cyclooxygenase-1 to exist constitutively and to be responsible for cytoprotection and hemostasis whereas cyclooxygenase-2 is inducible and involved in pain, inflammation and fever. In the meanwhile also constitutive cyclooxygenase-2 was discovered in various tissues. Cyclooxygenase-inhibitors may be divided into four groups: non selective ones (ibuprofen, diclofenac etc.), cyclooxygenase-1 selective inhibitors (SC-560), cyclooxygenase-2 preferential ones (meloxicam) and cyclooxygenase-2 selective inhibitors (celecoxib, rofecoxib, parecoxib). Selective cyclooxygenase-2-inhibitors in opposite to classic non steroidal anti-inflammatory drugs are without effect on bleeding time in therapeutic doses. The most important side effects of non steroidal anti-inflammatory drugs are bleeding, ulceration and perforation in the upper gastrointestinal tract and damage in the kidneys. Selective cyclooxygenase-2-inhibitors show less gastroduodenal ulcerations. Risk patients, however, still need gastroprotection during therapy with cyclooxygenase-2-inhibitors. In patients with low dose aspirin prophylaxis cyclooxygenase-2-inhibitors do not show any benefit compared to classic non steroidal anti-inflammatory drugs (CLASS-study). Less gastrointestinal side effects do not mean a higher overall safety benefit. Cardiovascular and thrombotic side effects of rofecoxib are higher than those of naproxen (VIGOR-study). Concerning valdecoxib, hypersensibilities are reported, probably due to its sulfonamidstructure. The same side effects are to be expected with its prodrug, parecoxib. Drug-drug interactions with cyclooxygenase-2-inhibitors and anticoagulant drugs are to be expected as well as other interactions with drugs, metabolised by the cytochrom P450 system.
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PMID:[Pharmacology of cyclooxygenase 2 inhibition]. 1270 61

A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to micro-opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and micro-opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histio-specific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.
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PMID:A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. 1505 13

The objective of this study was to evaluate the suitability of the early phase of adjuvant arthritis (pre-AA) as a model of inflammation for pharmacokinetic studies. Pre-AA is associated with little or no pain and discomfort as compared with fully developed adjuvant arthritis. Pre-AA was induced in male Sprague-Dawley rats with a tail base injection of Mycobacterium butyricum. Animals were monitored for symptoms of arthritis and levels of the proinflammatory mediators, serum nitrite, C-reactive protein (CRP), and tumor necrosis factor alpha (TNFalpha). On day 6, rats were administered single i.v. (2 mg/kg) or oral (20 mg/kg) doses of racemic verapamil, and S- and R-verapamil concentrations were determined by high-performance liquid chromatography. Hepatic cytochrome P450 (P450) content and verapamil protein binding were also measured. All experiments were carried out in both pre-AA and control rats. Serum nitrite, CRP, and TNFalpha levels were significantly elevated in pre-AA rats while signs of pain and arthritis were absent. Pre-AA also significantly elevated plasma concentrations of S- and R-verapamil after both i.v. and oral doses, due, likely, to decreased drug clearance. This was accompanied by a significant reduction in hepatic cytochrome P450, CYP3A, and CYP1A content as well as significantly reduced verapamil free fraction in pre-AA. The early phase of AA is marked by increased proinflammatory mediators and reduced verapamil clearance, as well as decreased hepatic P450 enzymes. Hence, pre-AA is a suitable model of inflammation for pharmacokinetic studies that avoids unnecessary exposure of animals to the pain and distress of fully developed adjuvant arthritis.
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PMID:Effect of early phase adjuvant arthritis on hepatic P450 enzymes and pharmacokinetics of verapamil: an alternative approach to the use of an animal model of inflammation for pharmacokinetic studies. 1565 40


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