Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats

Joel M Reid, Sarah A. Buhrow, Mary J. Kuffel, Lee Jia, Victoria J. Spanswick, John A. Hartley, David E. Thurston, Joseph E. Tomaszewski, Matthew M. Ames

Research output: Contribution to journalArticle

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Abstract

Purpose: The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501, SG2000) has potent in vitro antiproliferative activity and in vivo antitumor activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. The pharmacokinetics and in vitro metabolism of SJG-136 and as well as the feasibility of using the Comet assay to measure in vivo interstrand DNA cross-links, was assessed in the rat. Methods: SJG-136 pharmacokinetics and pharmacodynamics were characterized in rats following single-dose administration of 15 and 50 μg/kg or multiple-dose administration of 25 μg/kg/day for 5 days. DNA damage was measured in peripheral blood mononuclear cells using the Comet assay. SJG-136 oxidative metabolism was characterized in rat liver microsomes. Results: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m 2, and 1780 ml/m 2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. Conclusions: Plasma concentrations of SJG-136 associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant P450s catalyzing SJG-136 metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG-136 and is being used in clinical trials to monitor in vivo lesions produced by SJG-136.

Original languageEnglish (US)
Pages (from-to)777-786
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number3
DOIs
StatePublished - Sep 2011

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1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione)
Pharmacodynamics
Pharmacokinetics
Metabolism
Rats
DNA
Comet Assay
Cytochrome P-450 CYP3A
Assays
Liver Microsomes
Liver
pyrrolo(2,1-c)(1,4)benzodiazepine
DNA Damage
Protein Isoforms
Plasmas

Keywords

  • Comet assay
  • DNA damage
  • Metabolism
  • Pharmacodynamics
  • Pharmacokinetics
  • Pyrrolobenzodiazepine dimer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats. / Reid, Joel M; Buhrow, Sarah A.; Kuffel, Mary J.; Jia, Lee; Spanswick, Victoria J.; Hartley, John A.; Thurston, David E.; Tomaszewski, Joseph E.; Ames, Matthew M.

In: Cancer Chemotherapy and Pharmacology, Vol. 68, No. 3, 09.2011, p. 777-786.

Research output: Contribution to journalArticle

Reid, JM, Buhrow, SA, Kuffel, MJ, Jia, L, Spanswick, VJ, Hartley, JA, Thurston, DE, Tomaszewski, JE & Ames, MM 2011, 'Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats', Cancer Chemotherapy and Pharmacology, vol. 68, no. 3, pp. 777-786. https://doi.org/10.1007/s00280-010-1517-4
Reid, Joel M ; Buhrow, Sarah A. ; Kuffel, Mary J. ; Jia, Lee ; Spanswick, Victoria J. ; Hartley, John A. ; Thurston, David E. ; Tomaszewski, Joseph E. ; Ames, Matthew M. / Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 68, No. 3. pp. 777-786.
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abstract = "Purpose: The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501, SG2000) has potent in vitro antiproliferative activity and in vivo antitumor activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. The pharmacokinetics and in vitro metabolism of SJG-136 and as well as the feasibility of using the Comet assay to measure in vivo interstrand DNA cross-links, was assessed in the rat. Methods: SJG-136 pharmacokinetics and pharmacodynamics were characterized in rats following single-dose administration of 15 and 50 μg/kg or multiple-dose administration of 25 μg/kg/day for 5 days. DNA damage was measured in peripheral blood mononuclear cells using the Comet assay. SJG-136 oxidative metabolism was characterized in rat liver microsomes. Results: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m 2, and 1780 ml/m 2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. Conclusions: Plasma concentrations of SJG-136 associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant P450s catalyzing SJG-136 metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG-136 and is being used in clinical trials to monitor in vivo lesions produced by SJG-136.",
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author = "Reid, {Joel M} and Buhrow, {Sarah A.} and Kuffel, {Mary J.} and Lee Jia and Spanswick, {Victoria J.} and Hartley, {John A.} and Thurston, {David E.} and Tomaszewski, {Joseph E.} and Ames, {Matthew M.}",
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T1 - Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats

AU - Reid, Joel M

AU - Buhrow, Sarah A.

AU - Kuffel, Mary J.

AU - Jia, Lee

AU - Spanswick, Victoria J.

AU - Hartley, John A.

AU - Thurston, David E.

AU - Tomaszewski, Joseph E.

AU - Ames, Matthew M.

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N2 - Purpose: The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501, SG2000) has potent in vitro antiproliferative activity and in vivo antitumor activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. The pharmacokinetics and in vitro metabolism of SJG-136 and as well as the feasibility of using the Comet assay to measure in vivo interstrand DNA cross-links, was assessed in the rat. Methods: SJG-136 pharmacokinetics and pharmacodynamics were characterized in rats following single-dose administration of 15 and 50 μg/kg or multiple-dose administration of 25 μg/kg/day for 5 days. DNA damage was measured in peripheral blood mononuclear cells using the Comet assay. SJG-136 oxidative metabolism was characterized in rat liver microsomes. Results: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m 2, and 1780 ml/m 2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. Conclusions: Plasma concentrations of SJG-136 associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant P450s catalyzing SJG-136 metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG-136 and is being used in clinical trials to monitor in vivo lesions produced by SJG-136.

AB - Purpose: The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501, SG2000) has potent in vitro antiproliferative activity and in vivo antitumor activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. The pharmacokinetics and in vitro metabolism of SJG-136 and as well as the feasibility of using the Comet assay to measure in vivo interstrand DNA cross-links, was assessed in the rat. Methods: SJG-136 pharmacokinetics and pharmacodynamics were characterized in rats following single-dose administration of 15 and 50 μg/kg or multiple-dose administration of 25 μg/kg/day for 5 days. DNA damage was measured in peripheral blood mononuclear cells using the Comet assay. SJG-136 oxidative metabolism was characterized in rat liver microsomes. Results: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m 2, and 1780 ml/m 2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. Conclusions: Plasma concentrations of SJG-136 associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant P450s catalyzing SJG-136 metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG-136 and is being used in clinical trials to monitor in vivo lesions produced by SJG-136.

KW - Comet assay

KW - DNA damage

KW - Metabolism

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Pyrrolobenzodiazepine dimer

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