Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan.
OBJECTIVE
Melphalan is widely used in the treatment of multiple myeloma. Pharmacokinetics of this alkylating drug shows high inter-individual variability. As melphalan is a phenylalanine derivative, the pharmacokinetic variability may be determined by genetic polymorphisms in the L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8).


METHODS
Pharmacokinetics were analysed in 64 patients after first administration of intravenous melphalan. Severity of side effects was documented according to WHO criteria. Genomic DNA was analysed for polymorphisms in LAT1 and LAT2 by sequencing of the entire coding region, intron-exon boundaries and 2 kb upstream promoter region. Selected polymorphisms in the common heavy chain of both transporters, the protein 4F2hc (SLC3A2), were analysed by single nucleotide primer extension.


RESULTS
Melphalan pharmacokinetics was highly variable with up to 6.2-fold differences in total clearance. A total of 44 polymorphisms were identified in LAT1 and 21 polymorphisms in LAT2. From all variants, only five were in the coding region and only one heterozygous non-synonymous polymorphism (Ala94Thr) was found in LAT2. Numerous polymorphisms were found in the LAT1 and LAT2 5'-flanking regions but did not correlate with expression of the respective genes. No significant correlations could be observed between the polymorphisms in 4F2hc, LAT1, and LAT2 with melphalan pharmacokinetics or with melphalan side effects.


CONCLUSIONS
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.
Kühne
Annett
A
Department of Clinical Pharmacology, Georg-August-University Göttingen, Göttingen, Germany. akuehne@med.uni-goettingen.de
Kaiser
Rolf
R
Schirmer
Markus
M
Heider
Ulrike
U
Muhlke
Sabine
S
Niere
Wiebke
W
Overbeck
Tobias
T
Hohloch
Karin
K
Trümper
Lorenz
L
Sezer
Orhan
O
Brockmöller
Jürgen
J
D019943:Amino Acid Substitution; D027182:Amino Acid Transport System y+ / Q000235:genetics* / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000378:metabolism; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D007438:Introns; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008558:Melphalan / Q000009:adverse effects* / Q000493:pharmacokinetics*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
D027182:Amino Acid Transport System y+; D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027301:Fusion Regulatory Protein 1, Light Chains; D027283:Large Neutral Amino Acid-Transporter 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C420646:SLC7A8 protein, human; D008558:Melphalan