Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites
Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleo...
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MDPI AG
2022-12-01
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| author | Kannan Sridharan Ali Mohamed Qader Mustafa Hammad Anfal Jassim Diab Eltayeb Diab Betsy Abraham Hasan M. S. N. Hasan Sheikh Abdul Azeez Pasha Shamik Shah |
| author_facet | Kannan Sridharan Ali Mohamed Qader Mustafa Hammad Anfal Jassim Diab Eltayeb Diab Betsy Abraham Hasan M. S. N. Hasan Sheikh Abdul Azeez Pasha Shamik Shah |
| author_sort | Kannan Sridharan |
| collection | DOAJ |
| description | Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the CYP enzymes result in modified enzymatic activity. The present study was carried out to evaluate the prevalence of SNPs related to paracetamol metabolism and principal metabolites in critically ill patients, and those with chronic kidney disease. The present study is a cross-sectional study carried out in adults (>21 years) requiring intravenous paracetamol as part of their standard of care. Details regarding their demographics, and renal and liver function tests were collected. Blood was withdrawn for the analysis of paracetamol and their metabolites, and the SNPs of key CYP enzymes. Paracetamol/paracetamol glucuronide (P/PG), paracetamol/paracetamol sulphate (P/PS) and PG/PS were estimated. Acute liver injury (ALI) and renal dysfunction were defined using standard definitions. We observed a significant prevalence of SNPs in CYP1A2*1C, CYP3A4*3, CYP1A2*1K, CYP1A2*6, CYP2D6*10, and CYP2E1*2 amongst the 150 study participants. Those with CYP1A2*6 (CC genotype) were observed with significantly lower PG and PS concentrations, and a higher P/PS ratio; CYP2D6*10 (1/1 genotype) with a significantly lower PG concentration and a higher P/PG ratio; and CYP1A2*1K (CC genotype) was observed with a significantly higher PG/PS ratio. Good predictive accuracies were observed for determining the SNPs with the cut-off concentration of 0.29 μM for PS in determining CYP1A2*1K, 0.39 μM for PG and 0.32 μM for PS in determining CYP1A2*6 genotype, and 0.29 μM for PG in determining the CYP2D6*10 genotype. Patients with renal dysfunction were observed with significantly greater concentrations of paracetamol, PG and P/PS, and PG/PS ratios, with a lower concentration of PS. No significant differences were observed in any of the metabolites or metabolite ratios in patients with ALI. We have elucidated the prevalence of key CYP enzymes involved in acetaminophen metabolism in our population. Alterations in the metabolite concentrations and metabolic ratios were observed with SNPs, and in patients with renal dysfunction. Population toxicokinetic studies elucidating the dose-response relationship are essential to understand the optimized dose in this sub-population. |
| first_indexed | 2024-03-09T16:05:52Z |
| format | Article |
| id | doaj.art-1f50ae71d2a646d4934b57f7eed61a26 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T16:05:52Z |
| publishDate | 2022-12-01 |
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| spelling | doaj.art-1f50ae71d2a646d4934b57f7eed61a262023-11-24T16:38:01ZengMDPI AGMetabolites2218-19892022-12-011212123510.3390/metabo12121235Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its MetabolitesKannan Sridharan0Ali Mohamed Qader1Mustafa Hammad2Anfal Jassim3Diab Eltayeb Diab4Betsy Abraham5Hasan M. S. N. Hasan6Sheikh Abdul Azeez Pasha7Shamik Shah8Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama P.O. Box 26671, BahrainSalmaniya Medical Complex, Manama P.O. Box 26671, BahrainSalmaniya Medical Complex, Manama P.O. Box 26671, BahrainDepartment of Molecular Medicine, College of Medicine and Medical Sciences, Al-Jawhara Center, Arabian Gulf University, Manama P.O. Box 26671, BahrainDepartment of Molecular Medicine, College of Medicine and Medical Sciences, Al-Jawhara Center, Arabian Gulf University, Manama P.O. Box 26671, BahrainIntensive Care Unit, Salmaniya Medical Complex, Manama P.O. Box 26671, BahrainIntensive Care Unit, Salmaniya Medical Complex, Manama P.O. Box 26671, BahrainIntensive Care Unit, Salmaniya Medical Complex, Manama P.O. Box 26671, BahrainDepartment of Nephrology, Salmaniya Medical Complex, Manama P.O. Box 26671, BahrainIntravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the CYP enzymes result in modified enzymatic activity. The present study was carried out to evaluate the prevalence of SNPs related to paracetamol metabolism and principal metabolites in critically ill patients, and those with chronic kidney disease. The present study is a cross-sectional study carried out in adults (>21 years) requiring intravenous paracetamol as part of their standard of care. Details regarding their demographics, and renal and liver function tests were collected. Blood was withdrawn for the analysis of paracetamol and their metabolites, and the SNPs of key CYP enzymes. Paracetamol/paracetamol glucuronide (P/PG), paracetamol/paracetamol sulphate (P/PS) and PG/PS were estimated. Acute liver injury (ALI) and renal dysfunction were defined using standard definitions. We observed a significant prevalence of SNPs in CYP1A2*1C, CYP3A4*3, CYP1A2*1K, CYP1A2*6, CYP2D6*10, and CYP2E1*2 amongst the 150 study participants. Those with CYP1A2*6 (CC genotype) were observed with significantly lower PG and PS concentrations, and a higher P/PS ratio; CYP2D6*10 (1/1 genotype) with a significantly lower PG concentration and a higher P/PG ratio; and CYP1A2*1K (CC genotype) was observed with a significantly higher PG/PS ratio. Good predictive accuracies were observed for determining the SNPs with the cut-off concentration of 0.29 μM for PS in determining CYP1A2*1K, 0.39 μM for PG and 0.32 μM for PS in determining CYP1A2*6 genotype, and 0.29 μM for PG in determining the CYP2D6*10 genotype. Patients with renal dysfunction were observed with significantly greater concentrations of paracetamol, PG and P/PS, and PG/PS ratios, with a lower concentration of PS. No significant differences were observed in any of the metabolites or metabolite ratios in patients with ALI. We have elucidated the prevalence of key CYP enzymes involved in acetaminophen metabolism in our population. Alterations in the metabolite concentrations and metabolic ratios were observed with SNPs, and in patients with renal dysfunction. Population toxicokinetic studies elucidating the dose-response relationship are essential to understand the optimized dose in this sub-population.https://www.mdpi.com/2218-1989/12/12/1235paracetamolacetaminophenparacetamol sulphateparacetamol glucuronidepharmacogenetics |
| spellingShingle | Kannan Sridharan Ali Mohamed Qader Mustafa Hammad Anfal Jassim Diab Eltayeb Diab Betsy Abraham Hasan M. S. N. Hasan Sheikh Abdul Azeez Pasha Shamik Shah Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites Metabolites paracetamol acetaminophen paracetamol sulphate paracetamol glucuronide pharmacogenetics |
| title | Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites |
| title_full | Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites |
| title_fullStr | Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites |
| title_full_unstemmed | Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites |
| title_short | Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites |
| title_sort | evaluation of the association between single nucleotide polymorphisms of metabolizing enzymes with the serum concentration of paracetamol and its metabolites |
| topic | paracetamol acetaminophen paracetamol sulphate paracetamol glucuronide pharmacogenetics |
| url | https://www.mdpi.com/2218-1989/12/12/1235 |
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