The Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid: Systematic Review and Meta-analysis

Takuathung, Mingkwan Na; Sakuludomkan, Wannachai; Koonrungsesomboon, Nut

doi:10.1007/s40262-021-01037-7

Cited by 22 publications

(14 citation statements)

References 74 publications

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“… 20 According to earlier research on the immunosuppressant medication Mycophenolic acid, SLCO1B3 334T > G was shown to be strongly linked to adverse outcomes, although heterozygous carriers of SLCO1B3 334T > G had a lower chance of experiencing gastrointestinal side effects than wild-type people. 40 …”

Section: Discussionmentioning

confidence: 99%

Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients

Hamza¹,

Shouman²,

Abdelfattah³

et al. 2022

DDDT

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Background Imatinib is used to treat chronic myelogenous leukemia (CML). Variations in imatinib pharmacokinetics have been linked to genetic variations. That has an impact on imatinib response and adverse effects. Therefore, the aim of the study was to study bone pain as an adverse effect that occurs with imatinib and to investigate the risk factors for bone pain. Methods The relationship between the peak and trough plasma concentrations of imatinib with bone pain as one of the most frequently occurring adverse effects was examined. Multiple linear regression analysis and binary logistic regression analysis were used to measure the impact of various patients’ characteristics on both peak and trough imatinib concentrations and the risk of the occurrence of imatinib-induced bone pain. Results As a side effect of imatinib, approximately 15% of patients with CML who were taking it experienced bone pain. This side effect was linked to the imatinib peak and trough plasma levels. Imatinib trough concentration was also linked to gender and the gene SLCO1B3-334T > G (TT). There were significant associations between peak concentrations and gender as well as patient weight. Conclusion Higher peak and trough plasma concentrations of imatinib are linked with the risk of the occurrence of bone pain as a side effect of imatinib. Monitoring plasma concentrations of imatinib is useful to predict the bone pain of imatinib and to support quality of life in patients with CML.

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Section: Discussionmentioning

confidence: 99%

Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients

Hamza¹,

Shouman²,

Abdelfattah³

et al. 2022

DDDT

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“…Therefore, by controlling for rs6714486 and rs17868320, one controls also for several SNPs that were not directly genotyped. No consistent signal of association with MPA exposure has been found for several other UGT1A9 SNPs (rs6731242, rs13418420, rs3832043, rs2741049, rs13418420, rs17868323) [4,5,39,41]. Moreover, rs6714486 and rs17868320 are in LD with some of them (haplotypes UGT1A91v and *1w ) [40].…”

Section: Discussionmentioning

confidence: 99%

Loss of function ABCG2 c.421C>A (rs2231142) polymorphism increases steady-state exposure to mycophenolic acid in stable renal transplant recipients: exploratory matched cohort study

Trkulja¹

2022

Preprint

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Introduction. Polymorphism ABCG2 c.421C>A(rs2231142) results in a reduced activity of the important drug efflux transporter breast cancer resistance protein (BCRP/ABCG2). One study suggested that it may affect enterohepatic recirculation of mycophenolic acid (MPA). We evaluated the effect rs2231142 on steady-state exposure to MPA in renal transplant recipients.Methods . Consecutive, stable adult (age [?]16 years) renal transplant recipients on standard MPA-based immunosuppressant protocols (N=68, 43 co-treated with cyclosporine, 25 with tacrolimus) underwent routine therapeutic drug monitoring after a week of initial treatment, and were genotyped for ABCG2 c.421C>A and 11 polymorphisms in genes encoding enzymes and transporters implicated in MPA pharmacokinetics. ABCG2 c.421C>A variant vs. wild-type (wt) patients were matched in respect to demographic, biopharmaceutic and genetic variables (full optimal combined with exact matching) and compared for dose-adjusted

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“…UGT1A9 is a polymorphic enzyme. Significant variability in the pharmacokinetics of mycophenolic acid exists in subjects carrying different UGT1A9 genotypes ( Na Takuathung et al, 2021 ). Presumably, it may also be a factor responsible for the interindividual variation of ticagrelor.…”

Section: Discussionmentioning

confidence: 99%

“…and exogenous compounds (e.g., drugs, nondrug xenobiotics, etc.) are largely attributed to the glucuronidation catalyzed by UGTs isoforms (Miners and Mackenzie, 1991;Radominska-Pandya et al, 1999;Tukey and Strassburg, 2000). Currently, 19 functional human UGTs have been identified.…”

Section: Introductionmentioning

confidence: 99%

Contributions of UDP-Glucuronosyltransferases to Human Hepatic and Intestinal Metabolism of Ticagrelor and Inhibition of UGTs and Cytochrome P450 Enzymes by Ticagrelor and its Glucuronidated Metabolite

Liu

Hou

et al. 2021

Front. Pharmacol.

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Ticagrelor is the first reversibly binding, direct-acting, oral P2Y12 receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal microsomes (HIM), was well characterized in the current study. The inhibition potential of human major UGTs by ticagrelor and ticagrelor-O-glucuronide was explored. The inhibitory effects of ticagrelor-O-glucuronide on cytochrome P450s (CYPs) enzymes were investigated as well. Ticagrelor glucuronidation exhibits substrate inhibition kinetics in both HLM and HIM with apparent Km values of 5.65 and 2.52 μM, Vmax values of 8.03 and 0.90 pmol min−1·mg protein−1, Ksi values of 1,343.0 and 292.9 respectively. The in vitro intrinsic clearances (Vmax/Km) for ticagrelor glucuronidation by HLM and HIM were 1.42 and 0.36 μl min−1·mg protein−1, respectively. Study with recombinant human UGTs suggested that multiple UGT isoforms including UGT1A9, UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 are involved in the conversion of ticagrelor to ticagrelor-O-glucuronide with UGT1A9 showing highest catalytic activity. The results were further supported by the inhibition studies on ticagrelor glucuronidation with typical UGT inhibitors in pooled HLM and HIM. Little or no inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 by ticagrelor and ticagrelor-O-glucuronide was noted. Ticagrelor-O-glucuronide also exhibited limited inhibitory effects toward CYP2C8, CYP2D6 and CYP3A4. In contrast, ticagrelor-O-glucuronide weakly inhibited CYP2B6, CYP2C9 and CYP2C19 activity with apparent IC50 values of 45.0, 20.0 and 18.8 μM, respectively. The potential of ticagrelor-O-glucuronide to cause drug-drug interactions warrant further study.

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The Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid: Systematic Review and Meta-analysis

Cited by 22 publications

References 74 publications

Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients

Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients

Loss of function ABCG2 c.421C>A (rs2231142) polymorphism increases steady-state exposure to mycophenolic acid in stable renal transplant recipients: exploratory matched cohort study

Contributions of UDP-Glucuronosyltransferases to Human Hepatic and Intestinal Metabolism of Ticagrelor and Inhibition of UGTs and Cytochrome P450 Enzymes by Ticagrelor and its Glucuronidated Metabolite

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