Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan

Kühne, Annett; Kaiser, Rolf; Schirmer, Markus; Heider, Ulrike; Muhlke, S; Niere, W; Overbeck, Tobias R.; Hohloch, Karin; Trümper, Lorenz; Sezer, Orhan; Brockmöller, Jürgen

doi:10.1097/fpc.0b013e3280ea77cd

Cited by 33 publications

(26 citation statements)

References 38 publications

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“…The polymorphism 2677G>T/A of ABCB1 gene was recently correlated with increase in k a of GAB. Although LAT2 transporter activity has been associated with GAB absorption, its gene ( SLC7A8 ) is highly conserved and there are no studies showing that polymorphisms could change gene expression or transporter function . Studies showed that LAT1 transporter plays a role in GAB distribution through the blood‐brain and blood‐retinal barriers .…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Yamamoto

Benzi

Azeredo

et al. 2018

Basic Clin Pharma Tox

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Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role in GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from 53 patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy-Weinberg equilibrium. An one-compartment model with first-order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution, and clearance estimated were 0.44 h , 86 L, and 17.3 × (estimated glomerular filtration ratio/89.58) L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Yamamoto

Benzi

Azeredo

et al. 2018

Basic Clin Pharma Tox

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“…While our work was in progress, a similarly designed study was published that failed to detect an association between SNPs in the genes encoding LAT1, LAT2, and 4F2hc and gastrointestinal toxicity following HDM chemotherapy (17). Although the patient population used was more heterogeneous than the one in our study and included individuals with diseases other than multiple myeloma, the more likely reason for these discrepant results was the lack of representation in their analysis of SNPs from the very large first intron of SLC7A5 , such as rs4240803.…”

Section: Discussionmentioning

confidence: 99%

A Single Nucleotide Polymorphism in SLC7A5 Is Associated with Gastrointestinal Toxicity after High-Dose Melphalan and Autologous Stem Cell Transplantation for Multiple Myeloma

Giglia

White

Hart

et al. 2014

Biology of Blood and Marrow Transplantation

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Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant non-hematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to inter-individual differences in the development of gastrointestinal complications of HDM, we analyzed single-nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and twenty in SLC7A8 were genotyped. Multiple analyses indicated that one SNP in the first intron of SLC7A5, rs4240803, significantly associated with TPN use (OR= 0.45, 95% CI 0.25 – 0.79, p = 0.007). Further, every haplotype that correlated with TPN requirement incorporated this SNP. These results suggest that variability in melphalan transport impacts mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.

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“…Nearly half of these children died of brain herniation and many who survived were permanently disabled [2]. The Clinic for Special Children, built in 1989, has since become a medical home to 79 MSUD patients [5,6,42]. Early work at the Clinic was focused on integrating metabolic management into general pediatric practice [2,43].…”

Section: Discussionmentioning

confidence: 99%

Classical maple syrup urine disease and brain development: Principles of management and formula design

Strauss

Wardley

Robinson

et al. 2010

Molecular Genetics and Metabolism

176

150

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Branched-chain ketoacid dehydrogenase deficiency results in complex and volatile metabolic derangements that threaten brain development. Treatment for classical maple syrup urine disease (MSUD) should address this underlying physiology while also protecting children from nutrient deficiencies. Based on a 20-year experience managing 79 patients, we designed a study formula to (1) optimize transport of seven amino acids (Tyr, Trp, His, Met, Thr, Gln, Phe) that compete with branched-chain amino acids (BCAAs) for entry into the brain via a common transporter (LAT1), (2) compensate for episodic depletions of glutamine, glutamate, and alanine caused by reverse transamination, and (3) correct deficiencies of omega-3 essential fatty acids, zinc, and selenium widespread among MSUD patients. The formula was enriched with LAT1 amino acid substrates, glutamine, alanine, zinc, selenium, and alphalinolenic acid (18:3n – 3). Fifteen Old Order Mennonite children were started on study formula between birth and 34 months of age and seen at least monthly in the office. Amino acid levels were checked once weekly and more often during illnesses. All children grew and developed normally over a period of 14– 33 months. Energy demand, leucine tolerance, and protein accretion were tightly linked during periods of normal growth. Rapid shifts to net protein degradation occurred during illnesses. At baseline, most LAT1 substrates varied inversely with plasma leucine, and their calculated rates of brain uptake were 20–68% below normal. Treatment with study formula increased plasma concentrations of LAT1 substrates and normalized their calculated uptakes into the nervous system. Red cell membrane omega-3 polyunsaturated fatty acids and serum zinc and selenium levels increased on study formula. However, selenium and docosahexaenoic acid (22:6n – 3) levels remained below normal. During the study period, hospitalizations decreased from 0.35 to 0.14 per patient per year. There were 28 hospitalizations managed with MSUD hyperalimentation solution; 86% were precipitated by common infections, especially vomiting and gastroenteritis. The large majority of catabolic illnesses were managed successfully at home using ‘sickday’ formula and frequent amino acid monitoring. We conclude that the study formula is safe and effective for the treatment of classical MSUD. In principle, dietary enrichment protects the brain against deficiency of amino acids used for protein accretion, neurotransmitter synthesis, and methyl group transfer. Although the pathophysiology of MSUD can be addressed through rational formula design, this does not replace the need for vigilant clinical monitoring, frequent measurement of the complete amino acid profile, and ongoing dietary adjustments that match nutritional intake to the metabolic demands of growth and illness.

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Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan

Abstract: The study confirmed that these transporter genes are highly conserved, particularly in the coding sequences. Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan.

Cited by 33 publications

References 38 publications

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

A Single Nucleotide Polymorphism in SLC7A5 Is Associated with Gastrointestinal Toxicity after High-Dose Melphalan and Autologous Stem Cell Transplantation for Multiple Myeloma

Classical maple syrup urine disease and brain development: Principles of management and formula design

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