Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients

Thomas, Levin; Miraj, Sonal Sekhar; Mallayasamy, Surulivelrajan; Varma, Muralidhar; Sanju, Chidananda S V; Rao, Mahadev

doi:10.3390/antibiotics9060307

Cited by 15 publications

(18 citation statements)

References 92 publications

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“…An important enzyme in the metabolism of RIF is AADAC catalyzing its deacetylation to 25-deacetyl-RIF [7, 28, 29]. Polymorphic variations affecting this enzyme’s activity can also result in the accumulation of toxic substances and variations in RIF plasma concentrations that can affect the efficacy of this drug.…”

Section: Discussionmentioning

confidence: 99%

Allelic and Genotypic Frequencies of NAT2, CYP2E1 and AADAC genes in a cohort of Peruvian Tuberculosis Patients

Levano

Jaramillo‐Valverde

Tarazona

et al. 2021

Preprint

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Background: We determined the frequency of genetic polymorphisms in three anti-TB drug metabolic proteins previously reported: N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and arylacetamide deacetylase (AADAC) within a Peruvian population in a cohort of TB patients. We included 395 participants completed their anti-tuberculosis treatment. Results: ~74% of the participants are carriers of slow metabolizer genotypes: NAT2*5, NAT2*6 and NAT2*7, which increase the sensitivity of INH at low doses and increase the risk of drug-induced liver injuries. ~ 64% are homozygous for the wild-type CYP2E1*1A allele, which could increase the risk of hepatotoxicity. However, 16% had a NAT2 fast metabolizer phenotype which could increase the risk of acquiring resistance to INH, thereby increasing the risk of multidrug-resistant (MDR) or treatment failure. The frequency of rs1803155 (AADAC*2 allele) was higher (99.9%) in Peruvians than in in European American, African American, Japanese, and Korean populations. Conclusions: This high prevalence of slow metabolizers for Isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru. These data will help the Peruvian National Tuberculosis Control Program develop new strategies for therapies.

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Section: Discussionmentioning

confidence: 99%

Allelic and Genotypic Frequencies of NAT2, CYP2E1 and AADAC genes in a cohort of Peruvian Tuberculosis Patients

Levano

Jaramillo‐Valverde

Tarazona

et al. 2021

Preprint

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“…SLCO1B1 gene polymorphism may not be an important factor affecting the rifampicin concentration in Korean patients, but further studies with a larger population will be needed to validate these findings. Also, follow‐up studies exploring the SNPs of other genes encoding drug transporters and their transcriptional regulators, metabolic enzymes and pathway regulators are necessary to understand rifampicin PK in Korean TB patients 30 …”

Section: Discussionmentioning

confidence: 99%

Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis

Kim

Kwon

Chung

et al. 2021

Brit J Clinical Pharma

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Aims: Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB.Methods: From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored.Results: A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure.Conclusion: SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.

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“…Troglitazone is more dependent on CYP3A4, while tienilic acid, valproic acid, and diclofenac are more dependent on CYP2C9 [ 26 ]. Apart from CYP450, SNPs in the drug transporter and vitamin D pathways would also influence rifampicin pharmacokinetics and thus lead to an increased risk of DILI [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms

Liu

et al. 2021

Bioengineered

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The occurrence of antituberculosis drug-induced liver injury affects the effectiveness of antituberculosis treatments. Understanding the mechanism and risk factors of such liver injury may improve the outcomes of those patients who received antituberculosis treatments. In this study, 2,255 pulmonary tuberculosis patients were included. Their medical records were reviewed, questionnaire surveys, liver function tests at the end of February (including patients with uncomfortable symptoms during the intensive treatment period), and blood samples were saved. Afterward, cases of liver damage were determined using Chinese liver damage criteria. The genotype of all participants was determined using the PCR-LDR method. Finally, the association between genetic polymorphism and ATB-DILI susceptibility was assessed using the univariate Logistic regression models. Among the 2,255 tuberculosis patients who received rifampicin, 612 (27.1%) had antituberculosis drug-induced liver injury. We observed higher proportions of older age, male, and lower levels of AST, ALT, and TBil among patients with liver injury. Results of univariate of logistic regression models showed that patients with CYP2C19 were more likely to have liver injury compared with no such genotypes patients (all P < 0.05). Patients with tuberculosis with older age and genetic polymorphism of CYP3A4, CYP2C9, and CYP2C19 who received long-term rifampicin treatment were more likely to have antituberculosis drug-induced liver injury. It is important for healthcare providers to carefully evaluate and monitor rifampicin use for these patients.

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Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients

Cited by 15 publications

References 92 publications

Allelic and Genotypic Frequencies of NAT2, CYP2E1 and AADAC genes in a cohort of Peruvian Tuberculosis Patients

Allelic and Genotypic Frequencies of NAT2, CYP2E1 and AADAC genes in a cohort of Peruvian Tuberculosis Patients

Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis

Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms

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