Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients

Zhou, Lingyun; Zuo, Xiaoxia; Chen, K.; Wang, J.-L.; Chen, Q.-J.; Zhou, Yanan; Yuan, Hong; Ma, Yongmin; Zhu, Lin; Peng, Yuyao; Ming, Yingzi

doi:10.1111/jcpt.12394

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…9 This finding is closely related to the differences in the genes related to drug metabolism in different individuals, mainly those genes related to the cytochrome CYP3A metabolizing enzyme and the multiple P-gp encoded by the drug resistance gene MDR1. 10 The CYP3A4*18B mutation enhances CYP3A4 enzyme activity, leading to a decrease in the C0/D of tacrolimus in patients carrying this allele, [11][12][13] and the present study confirmed a faster metabolism in CYP3A4*18B-expressing patients than in nonexpressing patients among healthy subjects. CYP3A5*3 has a high frequency of mutation in the Chinese population; CYP3A5*3/*3 is the most common mutant, and patients with CYP3A5-expressing genotypes (*1/*1 and *1/*3) metabolize tacrolimus more rapidly than patients with CYP3A5-nonexpressing genotypes (*3/*3).…”

Section: Correlations Between Indicators and Pharmacokinetic Parameterssupporting

confidence: 80%

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

SHEN,

Liu,

Zhang

et al. 2024

Preprint

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Aims: To investigate the effects of the CYP3A4*18B, CYP3A5*3, and MDR1C3435T gene polymorphisms on the pharmacokinetics of tacrolimus in healthy Chinese subjects. Methods: Thirty healthy Chinese subjects received single oral doses of 5 mg tacrolimus and were genotyped for CYP3A4*18B, CYP3A5*3, and MDR1C3435T using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The blood concentrations of tacrolimus were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS) up to 96 h after dosing. Results: The mean tacrolimus AUC0-96, AUC0-∞ and Cmax for the CYP3A4*1/*1 carriers were 282.81±202.13 ng·h·mL-1, 308.68±211.16 ng·h·mL-1 and 38.05±30.30 ng·mL-1, respectively, which were 3.96-fold, 3.70-fold and 3.88-fold greater than those of the CYP3A4*18B/*18B carriers (71.39±21.61 ng·h·mL-1, 83.38±29.00 ng·h·mL-1 and 9.80±2.60 ng·mL-1, respectively) (P= 0.001, 0.001 and 0.004, respectively). Similarly, the AUC0–96, AUC0-∞ and Cmax for the CYP3A5*3/*3 carriers were 238.27±178.82 ng·h·mL-1, 263.78±190.72 ng·h·mL-1 and 32.53±24.52 ng·mL-1, respectively, which were 2.52-, 2.48- and 2.27-fold greater than those of the CYP3A5*1 carriers (94.69±37.70 ng·h·mL-1, 106.28±41.46 ng·h·mL-1 and 14.30±5.77 ng·mL-1, respectively) (P=0.001, 0.001 and 0.004, respectively). Although there were no significant differences in pharmacokinetics among MDR1C3435T genotypes (P>0.05), the Tmax for MDR1 CC (1.25±0.27 h) homozygotes in CYP3A4 expressers (*18B/*18B or *1/*18B genotype) was much lower than that for the MDR1 T carriers (1.82±0.72 h) (P<0.05). In addition, sex, age, alanine aminotransferase (ALT) level, haematocrit (HCT) level, serum creatinine (SCr) level, gamma-glutamyl transferase (GGT) level, and CYP3A4*18B and CYP3A5*3 gene polymorphisms affected the pharmacokinetics of tacrolimus. Conclusions: CYP3A4*18B and CYP3A5*3 are important genetic factors influencing the pharmacokinetics of tacrolimus in the Chinese population.

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Section: Correlations Between Indicators and Pharmacokinetic Parameterssupporting

confidence: 80%

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

SHEN,

Liu,

Zhang

et al. 2024

Preprint

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“…In addition to the calculation results, it was discovered that the rs2242480 (C) allele was correlated with the rs776746 (C) allele, and the rs 2242480 (T) allele was also found to be correlated with the rs776746 (T) allele. The study by Zhou et al [7]. showed a strong linkage disequilibrium between CYP3A4*1G and CYP3A5*3 in the Chinese population.…”

Section: Resultsmentioning

confidence: 95%

“…It is well known that the presence of the CYP3A4*1G allele causes changes in the pharmacokinetic profile of some drugs. For example, a study by Zhou et al [7]. showed that the concentrations of diltiazem and its primary metabolites were strongly influenced by the CYP3A4*1G allele [7].…”

Section: Resultsmentioning

confidence: 99%

“…For example, a study by Zhou et al [7]. showed that the concentrations of diltiazem and its primary metabolites were strongly influenced by the CYP3A4*1G allele [7]. The average area under the plasma concentration-time curve of atorvastatin was 36% and 25% lower in CYP3A4*1G/*1G than in the wild-type or *1/*1G genotype, respectively [21].…”

Section: Resultsmentioning

confidence: 99%

“…Individuals with CYP3A4*1G showed variations in the pharmacokinetic profiles of fentanyl, tacrolimus, diltiazem, sufentanil, and tylerdipine hydrochloride [5][6][7][8][9]. An increased risk of breast cancer occurrence is known to be associated with CYP3A4*1G polymorphism [10].…”

Section: Introductionmentioning

confidence: 99%

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The Genetic Polymorphisms of CYP3A41G and CYP3A53 in Javanese Indonesian Population

Atmaja,

Rawar,

Kristiyani

et al. 2024

J.Trop.Life.Science

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Polymorphisms of CYP3A4*1G and CYP3A5*3 affect the pharmacokinetic profile of various drugs, e.g., fentanyl, tacrolimus, diltiazem, simvastatin. Tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) is a simple and economical method for SNP determination. The polymorphisms in the CYP3A4*1G and CYP3A5*3 genes have not yet been examined using this method in Javanese Indonesian. Our aim was to determine the frequency of polymorphisms in the CYP3A4*1G and CYP3A5*3 genes in Indonesian Javanese using the ARMS-PCR method. Eighty-six patients at the Kalasan Community Health Centre in Yogyakarta, Indonesia, were chosen based on the inclusion criteria, which is Javanese ancestry. They gave their informed consent to blood collection by completing a form. Genetic variants were detected using Tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR). The chi-square test was used to determine genotype deviations from Hardy-Weinberg equilibrium, with a significant threshold of 0.05. For homozygous wild types, CYP3A4 *1/*1 dominated overall among study participants (73.35%), whereas for CYP3A5*3/*3, homozygous mutants were more prevalent (83.72%). Hardy-Weinberg equilibrium is consistent with genotype frequencies (p > 0.005). One participant carried a homozygous mutation for both CYP3A4*1G and CYP3A5*3, while the other 49 subjects were heterozygous for CYP3A4*1G and homozygous mutant for CYP3A5*3, which is the highest number of SNP combinations. The findings of the current investigation demonstrate that the population has the highest proportion of homozygous CYP3A4*1G wild-types (CYP3A4*1/*1) and homozygous mutants for CYP3A5*3 (CYP3A5*3/*3)

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Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients

Guan

et al. 2017

Eur J Drug Metab Pharmacokinet

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Significant impacts of CYP3A41G and CYP3A53 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients

Abstract: The CYP3A41G and CYP3A53 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.

Cited by 9 publications

References 34 publications

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

The Genetic Polymorphisms of CYP3A41G and CYP3A53 in Javanese Indonesian Population

Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients

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Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients

Abstract: The CYP3A4*1G and CYP3A5*3 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.

Cited by 9 publications

References 34 publications

CYP3A4*18B, CYP3A5*3, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

CYP3A4*18B, CYP3A5*3, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

The Genetic Polymorphisms of CYP3A4*1G and CYP3A5*3 in Javanese Indonesian Population

Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients

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Product

Resources

About

Significant impacts of CYP3A41G and CYP3A53 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients

Abstract: The CYP3A41G and CYP3A53 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

CYP3A418B, CYP3A53, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

The Genetic Polymorphisms of CYP3A41G and CYP3A53 in Javanese Indonesian Population