Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes

William C. Zamboni, Ramesh K. Ramanathan, Howard L. McLeod, Sridhar Mani, Douglas M. Potter, Sandra Strychor, Lauren J. Maruca, Cristi R. King, Laura L. Jung, Robert A. Parise, Merrill J. Egorin, Todd A. Davis, Sharon Marsh

Research output: Contribution to journalArticle

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Abstract

Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. Results: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL·h and 51.1 ng/mL·h, respectively (P = 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 ± 78.3 ng/mL·h and 129.0 ± 90.5 ng/mL·h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.

Original languageEnglish (US)
Pages (from-to)393-401
Number of pages9
JournalInvestigational New Drugs
Volume24
Issue number5
DOIs
StatePublished - Sep 2006

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9-aminocamptothecin
ATP-Binding Cassette Transporters
Genotype
Pharmacokinetics
Camptothecin
Area Under Curve
rubitecan

Keywords

  • 9AC
  • 9NC
  • ABC transporters
  • Genotyping
  • Pharmacogenetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes. / Zamboni, William C.; Ramanathan, Ramesh K.; McLeod, Howard L.; Mani, Sridhar; Potter, Douglas M.; Strychor, Sandra; Maruca, Lauren J.; King, Cristi R.; Jung, Laura L.; Parise, Robert A.; Egorin, Merrill J.; Davis, Todd A.; Marsh, Sharon.

In: Investigational New Drugs, Vol. 24, No. 5, 09.2006, p. 393-401.

Research output: Contribution to journalArticle

Zamboni, WC, Ramanathan, RK, McLeod, HL, Mani, S, Potter, DM, Strychor, S, Maruca, LJ, King, CR, Jung, LL, Parise, RA, Egorin, MJ, Davis, TA & Marsh, S 2006, 'Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes', Investigational New Drugs, vol. 24, no. 5, pp. 393-401. https://doi.org/10.1007/s10637-006-6335-5
Zamboni, William C. ; Ramanathan, Ramesh K. ; McLeod, Howard L. ; Mani, Sridhar ; Potter, Douglas M. ; Strychor, Sandra ; Maruca, Lauren J. ; King, Cristi R. ; Jung, Laura L. ; Parise, Robert A. ; Egorin, Merrill J. ; Davis, Todd A. ; Marsh, Sharon. / Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes. In: Investigational New Drugs. 2006 ; Vol. 24, No. 5. pp. 393-401.
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abstract = "Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. Results: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL·h and 51.1 ng/mL·h, respectively (P = 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 ± 78.3 ng/mL·h and 129.0 ± 90.5 ng/mL·h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.",
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T1 - Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes

AU - Zamboni, William C.

AU - Ramanathan, Ramesh K.

AU - McLeod, Howard L.

AU - Mani, Sridhar

AU - Potter, Douglas M.

AU - Strychor, Sandra

AU - Maruca, Lauren J.

AU - King, Cristi R.

AU - Jung, Laura L.

AU - Parise, Robert A.

AU - Egorin, Merrill J.

AU - Davis, Todd A.

AU - Marsh, Sharon

PY - 2006/9

Y1 - 2006/9

N2 - Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. Results: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL·h and 51.1 ng/mL·h, respectively (P = 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 ± 78.3 ng/mL·h and 129.0 ± 90.5 ng/mL·h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.

AB - Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. Results: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL·h and 51.1 ng/mL·h, respectively (P = 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 ± 78.3 ng/mL·h and 129.0 ± 90.5 ng/mL·h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.

KW - 9AC

KW - 9NC

KW - ABC transporters

KW - Genotyping

KW - Pharmacogenetics

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