The impact of diuretic use and <i>ABCG2</i> genotype on the predictive performance of a published allopurinol dosing tool

Wright, Daniel F. B.; Dalbeth, Nicola; Phipps‐Green, Amanda; Merriman, Tony R.; Barclay, Murray L.; Drake, Jill; Tan, Paul; Horne, Anne; Stamp, Lisa K.

doi:10.1111/bcp.13516

Cited by 12 publications

(12 citation statements)

References 23 publications

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“…The variant rs2231142 affects the nucleotide-binding domain of the transporter and decreases protein levels because it promotes its degradation. It has been recommended that patients with gout carrying the rs223114 variant in ABCG2 take a higher dose of allopurinol than patients with the wild-type genotype [53]. However, this recommendation should be reviewed, because the dosage of the drug is based on urate plasma levels, which as a BCRP substrate can be influenced by changes in the expression and activity of this pump.…”

Section: Breast Cancer Resistance Protein (Bcrp)mentioning

confidence: 99%

Role of Genetic Variations in the Hepatic Handling of Drugs

Marin

Serrano

Monte

et al. 2020

IJMS

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The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

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Section: Breast Cancer Resistance Protein (Bcrp)mentioning

confidence: 99%

Role of Genetic Variations in the Hepatic Handling of Drugs

Marin

Serrano

Monte

et al. 2020

IJMS

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“…3 A number of variables have been reported to influence the dose of allopurinol required to reach target urate, including pre-urate lowering SU concentration, 4 renal function, weight, diuretic use, and the presence of the lysine (K) allele of ABCG2 Q141K, which encodes a urate efflux transporter in the kidneys, liver, and intestine. [5][6][7] Given the variability in allopurinol dose required to reach target urate, the ability to measure plasma oxypurinol to guide allopurinol dosing may be an advantage. Previous studies examining the relationship between oxypurinol and SU concentrations have been conflicting, with some showing no relationship 8 and some an inverse relationship.…”

Section: Study Highlightsmentioning

confidence: 99%

“…Lack of a standardized allopurinol dose, with marked interindividual variability in the dose required to achieve target urate also contributes to failure to reach target urate . A number of variables have been reported to influence the dose of allopurinol required to reach target urate, including pre‐urate lowering SU concentration, renal function, weight, diuretic use, and the presence of the lysine (K) allele of ABCG2 Q141K, which encodes a urate efflux transporter in the kidneys, liver, and intestine …”

mentioning

confidence: 99%

Relationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration

Stamp

Chapman

Barclay

et al. 2019

Clinical Translational Sci

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The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24‐month open, randomized, controlled, parallel‐group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic (ROC) curves were used to identify a minimum oxypurinol concentration predictive of SU < 6 mg/dL. There was a wide range of SU concentrations for each allopurinol dose. The relationship between sensitivity to allopurinol and allopurinol metabolism for each 100 mg allopurinol dose increase varied between individuals. Body mass index (P = 0.023), creatinine clearance (CrCL; P = 0.037), ABCG2 Q141K (P = 0.019), and SU (P = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 μmol/L, but predictive accuracy was poor (ROC curve area under the curve (AUC) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on CrCL and cannot reliably predict SU target. Other variables, including ABCG2 Q141K genotype, impact on sensitivity to allopurinol (ACTRN12611000845932).

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“…Genome‐wide association studies (GWAS) provide insights on how single nucleotide polymorphisms (SNPs) in key transporter genes can impact treatment outcomes. The ABCG2 (BCRP) rs2231142C>A is associated with SU‐lowering response to allopurinol 22–25 and has been suggested as a guide to improve drug dosage and/or selection by identifying patients in need of alternative therapeutic approaches 26 . The SLC22A12 (URAT1) rs505802C>T is not only associated with the risk of hyperuricemia, 27 but also importantly associated with the exposure of serum oxypurinol, the active metabolite of allopurinol 28 .…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics, pharmacodynamics and pharmacogenetics modelling of oxypurinol in Hmong adults with gout and/or hyperuricemia

Wen

Brundage

Roman

et al. 2023

Brit J Clinical Pharma

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AimsThe aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU).MethodsHmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non‐linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model.ResultsA one‐compartment model with first‐order absorption and elimination best described the oxypurinol concentration–time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady‐state oxypurinol concentrations. Fat‐free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (−0.27 per A allele, 95% CI −0.38, −0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications.ConclusionsThe proposed allopurinol dosing guide uses individuals' fat‐free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

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The impact of diuretic use and ABCG2 genotype on the predictive performance of a published allopurinol dosing tool

Abstract: The dosing tool produced acceptable maintenance dose predictions for patients not taking diuretics. Inclusion of ABCG2 genotype and a revised adjustment for diuretics would further improve the performance of the dosing tool.

Cited by 12 publications

References 23 publications

Role of Genetic Variations in the Hepatic Handling of Drugs

Role of Genetic Variations in the Hepatic Handling of Drugs

Relationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration

Population pharmacokinetics, pharmacodynamics and pharmacogenetics modelling of oxypurinol in Hmong adults with gout and/or hyperuricemia

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