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Medicina (Kaunas, Lithuania) Nov 2023: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases....
: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases. Disease-related polymorphisms can be observed within the gene. The two most important are Ser49Gly and Arg389Gly, and they influence the treatment efficacy. The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), which is involved in phase I metabolism of almost 25% of clinically important drugs, including antiarrhythmic drugs. A study was conducted to detect the and gene polymorphisms. : The material for the test was whole blood from 30 patients with ventricular and supraventricular tachycardia and 20 controls. The samples were obtained from the Department of Pediatric Cardiology. The first to be made was the extraction of DNA using a GeneMATRIX Quick Blood DNA Purification Kit from EURx. The selected and gene polymorphisms were detected by high-resolution melting polymerase chain reaction (HRM-PCR) analysis. : Based on the analysis of melt profile data for each PCR product, the identification of polymorphisms was carried out. Heterozygotes and homozygotes were found in the examined alleles. : The frequency of the Arg389Gly polymorphism differs statistically significantly between the control group and patients with supraventricular and ventricular arrhythmias, as well as between these two groups of patients. Moreover, the Arg389Gly polymorphism was statistically more prevalent in the group of girls with SVT arrhythmia compared to girls with VT. A few carriers of homozygous and heterozygous systems of the S49G polymorphism were detected among patients with arrhythmias, as well as control group. The percentage of individuals carrying the allele as either homozygous or heterozygous was observed in the study and control groups. The high prevalence of the allele carriers in both groups prompts the optimization of beta-1 blocker therapy.
Topics: Child; Female; Humans; Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Cytochrome P-450 CYP2D6; DNA; Polymorphism, Genetic; Receptors, Adrenergic, beta-1
PubMed: 38138160
DOI: 10.3390/medicina59122057 -
British Medical Journal Jan 1968
PubMed: 20791433
DOI: No ID Found -
Drug Metabolism and Disposition: the... Jul 2022Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and...
Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and antipsychotics, and its activity varies considerably on a population basis primary due to genetic variation. CYP2D6 phenotype can be assessed following administration of an exogenous probe compound, such as dextromethorphan or debrisoquine, but use of a biomarker that does not require administration of an exogenous compound ( drug) has considerable appeal for assessing CYP2D6 activity in vulnerable populations, such as children. The goal of this study was to isolate, purify and identify an "endogenous" urinary biomarker (M1; m/z 444.3102) of CYP2D6 activity reported previously. Several chromatographic separation techniques (reverse phase HPLC, cation exchange and analytical reverse phase UPLC) were used to isolate and purify 96 μg of M1 from 40 L of urine. Subsequently, 1D and 2D NMR, and functional group modification reactions were used to elucidate its structure. Analysis of mass spectrometry and NMR data revealed M1 to have similar spectroscopic features to the nitrogen-containing steroidal alkaloid, solanidine. 2D NMR characterization by HMBC, COSY, TOCSY, and HSQC-TOCSY proved to be invaluable in the structural elucidation of M1; derivatization of M1 revealed the presence of two carboxylic acid moieties. M1 was determined to be a steroidal alkaloid with a solanidine backbone that had undergone C-C bond scission to yield 3,4-seco-solanidine-3,4-dioic acid (SSDA). SSDA may have value as a dietary biomarker of CYP2D6 activity in populations where potato consumption is common. Endogenous biomarkers of processes involved in drug disposition and response may allow improved individualization of drug treatment, especially in vulnerable populations, such as children. Given that several CYP2D6 substrates are commonly used in pediatrics and the ubiquitous nature of potato consumption in western diets, SSDA has considerable appeal as non-invasive biomarker of CYP2D6 activity to guide treatment with CYP2D6 substrates in children and adults.
PubMed: 35878926
DOI: 10.1124/dmd.122.000957 -
British Journal of Clinical Pharmacology 1984Most beta-adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed. The AUC and half-life of...
Most beta-adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed. The AUC and half-life of metoprolol were considerably greater in poor metabolisers (PM) of debrisoquine than in extensive metabolisers (EM). Metoprolol alpha-hydroxylation is impaired and O-dealkylation must also be affected. Polymorphism in the former route has been demonstrated in a population of 143 patients to be directly related to debrisoquine phenotype. Bufuralol AUC and half-life are much higher in PM than EM subjects. Hydroxylation at the 1 and 4 positions are affected. Genetic polymorphism for 1-hydroxylation has been shown in family and population studies. Propranolol 4-hydroxylation is defective in PM subjects of debrisoquine but propranolol AUC is not related to phenotype, presumably because other major pathways are unaffected. Oxidation phenotype correlates well with intensity and duration of beta-adrenoceptor blockade after metoprolol, PM subjects requiring only once-daily dosing. However, in EM subjects twice-daily dosing is required even if slow release preparations are used, since plasma metoprolol concentrations may remain negligible 24 h after dosing. The beta-adrenoceptor blocking effects of propranolol and bufuralol are unlikely to be influenced by oxidation status. Anecdotal reports of toxicity arising in PM subjects taking metoprolol or propranolol need to be substantiated. However, vomiting after the administration of bufuralol often occurs in poor metabolisers. Metabolic interactions with drugs sharing the same enzyme system are discussed. Debrisoquine and bufuralol competitively inhibit each other's metabolism in vitro. (ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adrenergic beta-Antagonists; Biotransformation; Drug Interactions; Ethanolamines; Heart Rate; Humans; Metoprolol; Propranolol
PubMed: 6146335
DOI: 10.1111/j.1365-2125.1984.tb02423.x -
Stem Cells Translational Medicine Jan 2017Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ....
Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ. Donor scarcity and the necessity for immunosuppression limit one effective therapy, orthotopic liver transplantation. But in some conditions such as inborn errors of metabolism or transient states of liver insufficiency, patients may be salvaged by providing partial quantities of functional liver tissue. After transplanting multicellular liver organoid units composed of a heterogeneous cellular population that includes adult stem and progenitor cells, both mouse and human tissue-engineered liver (TELi) form in vivo. TELi contains normal liver components such as hepatocytes with albumin expression, CK19-expressing bile ducts and vascular structures with α-smooth muscle actin expression, desmin-expressing stellate cells, and CD31-expressing endothelial cells. At 4 weeks, TELi contains proliferating albumin-expressing cells and identification of β2-microglobulin-expressing cells demonstrates that the majority of human TELi is composed of transplanted human cells. Human albumin is detected in the host mouse serum, indicating in vivo secretory function. Liquid chromatography/mass spectrometric analysis of mouse serum after debrisoquine administration is followed by a significant increase in the level of the human metabolite, 4-OH-debrisoquine, which supports the metabolic and xenobiotic capability of human TELi in vivo. Implanted TELi grew in a mouse model of inducible liver failure. Stem Cells Translational Medicine 2017;6:238-248.
Topics: Adult Stem Cells; Animals; Arginase; Cell Proliferation; Disease Models, Animal; Female; Hepatocytes; Humans; Liver; Mice, SCID; Organoids; Tissue Engineering
PubMed: 28170183
DOI: 10.5966/sctm.2016-0205 -
Anesthesiology Oct 1988The metabolism of alfentanil was studied in three healthy subjects after a 1-h infusion of 2.5 mg alfentanil-3H. One of the subjects was a poor hydroxylator of...
The metabolism of alfentanil was studied in three healthy subjects after a 1-h infusion of 2.5 mg alfentanil-3H. One of the subjects was a poor hydroxylator of debrisoquine. Pharmacokinetic parameters were similar in the three subjects and were in the same range as those reported for volunteers. The majority of the administered radioactivity was excreted in the urine (90% of the dose), but unchanged alfentanil represented only 0.16-0.47% of the dose. Alfentanil and metabolites were characterized by HPLC co-chromatography with reference compounds and/or by mass spectrometry and quantified by GLC and radio-HPLC. The main metabolic pathway was N-dealkylation at the piperidine nitrogen, with formation of noralfentanil (30% of the dose). Other Phase I pathways were aromatic hydroxylation, N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, O-demethylation, and amide hydrolysis followed by N-acetylation. Glucuronic acid conjugation of aromatic or aliphatic hydroxyl functions was the main Phase II pathway. The second major metabolite was the glucuronide of N-(4-hydroxyphenyl) propanamide (14% of the dose). The metabolite pattern in these subjects was qualitatively very similar to that described previously in rats and dogs. Differences in the mass balance of urinary metabolites between the three subjects were very small, and there was no qualitative or quantitative evidence for a deficiency in the metabolism of alfentanil in the subject who was a poor metabolizer of debrisoquine.
Topics: Alfentanil; Chromatography, High Pressure Liquid; Fentanyl; Humans; Male; Mass Spectrometry; Time Factors
PubMed: 3140690
DOI: 10.1097/00000542-198810000-00012 -
Acta Pharmacologica Sinica Mar 2001To compare the level and/or activity of several important cytochrome P-450 (CYP) enzymes in liver microsomes prepared from different Chinese subjects. (Comparative Study)
Comparative Study
AIM
To compare the level and/or activity of several important cytochrome P-450 (CYP) enzymes in liver microsomes prepared from different Chinese subjects.
METHODS
Individual CYP contents, including CYP1A2, CYP2C9, and CYP3A4, in liver microsomes of 17 Han, 17 Zhuang, and 8 Miao subjects were determined by using Western blot analysis and densitometric scanning. The substrates for measuring the activity of individual CYP in vitro included phenacetin, tolbutamide, debrisoquine, and omeprazole.
RESULTS
There was a large interindividual variability in the content and activity of CYP1A2, 2C9 and 3A4. And the activity of CYP2D6 also varied greatly between individual samples. CYP3A4 (32 %) is the most abundant CYP in Chinese liver microsomes, and the levels of CYP2C9 (19 %) and CYP1A2 (16 %) were also considerable. No clear ethnic, sex- and age-related differences in individual CYP content and catalytic activity were detected in 42 Chinese liver samples, except that there were somewhat ethnic and sex-related differences in the content and activity of CYP1A2. Good correlation between enzyme protein content and activity was found for CYP1A2, 2C9 and 3A4.
CONCLUSION
Our results may provide useful information for the study of drug metabolism by liver microsomes in Chinese.
Topics: Aryl Hydrocarbon Hydroxylases; Asian People; China; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Ethnicity; Female; Humans; Male; Microsomes, Liver; Sex Factors
PubMed: 11742579
DOI: No ID Found -
American Journal of Human Genetics Feb 1997
Review
Topics: Acetylation; Animals; Arylamine N-Acetyltransferase; Bioethics; Cytochrome P-450 CYP2D6; Debrisoquin; Diet; Disease Susceptibility; Ethnicity; Glucosephosphate Dehydrogenase; Humans; Neoplasms; Oxidation-Reduction; Polymorphism, Genetic
PubMed: 9012398
DOI: No ID Found -
Drug Metabolism and Pharmacokinetics 2010The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development.... (Review)
Review
The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.
Topics: Animals; Cytochrome P-450 Enzyme System; Debrisoquin; Government Regulation; Hepatocytes; Humans; Liver; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Mice; Models, Animal; Pharmaceutical Preparations; Rats; Transplantation Chimera; Warfarin
PubMed: 20610881
DOI: 10.2133/dmpk.25.223 -
British Journal of Clinical Pharmacology Jun 19911. The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides... (Comparative Study)
Comparative Study
1. The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2. The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 +/- 340 nmol l-1 h, 2.58 +/- 0.57 h and 2.02 +/- 0.73 l h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3. PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P less than 0.0001), and lower partial metabolic clearance by O-demethylation (P less than 0.0001). In contrast, the PM had higher AUC of NC (P less than 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4. Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N- and O-demethylations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Administration, Oral; Adult; Codeine; Debrisoquin; Female; Half-Life; Humans; Hydroxylation; Male; Middle Aged; Phenotype; Reference Values; White People
PubMed: 1867957
DOI: 10.1111/j.1365-2125.1991.tb05585.x