Irinotecan pathway genotype analysis to predict pharmacokinetics.
OBJECTIVE
The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan.


METHODS
Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control.


RESULTS
Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22).


CONCLUSIONS
It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.
Mathijssen
Ron H J
RH
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 3075 EA Rotterdam, the Netherlands.
Marsh
Sharon
S
Karlsson
Mats O
MO
Xie
Rujia
R
Baker
Sharyn D
SD
Verweij
Jaap
J
Sparreboom
Alex
A
McLeod
Howard L
HL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D043182:Carboxylesterase / Q000235:genetics; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005965:Glucuronates / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000235:genetics; D006720:Homozygote; D006801:Humans; D000077146:Irinotecan; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D000076105:X-ray Repair Cross Complementing Protein 1; D000099148:UGT1A1 Enzyme
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D002166:Camptothecin; D043182:Carboxylesterase; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D005965:Glucuronates; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C000619371:XRCC1 protein, human; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C421109:multidrug resistance-associated protein 1