Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates

Susan M. Blaney, Chris Takimoto, Daryl J. Murry, Nancy Kuttesch, Cynthia McCully, Diane E. Cole, Karen Godwin, Frank M. Balis

Research output: Contribution to journalArticle

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Abstract

Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 1/kg per h, a volume of distribution at steady state (Vd(ss)) of 1.6 ± 0.7 l/kg and a half-life (t( 1/4 )) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC(P)) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vd(ss) was 7.1 ± 1.3 l/kg, and the t( 1/4 ) was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be 18%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.

Original languageEnglish (US)
Pages (from-to)464-468
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume41
Issue number6
DOIs
StatePublished - Apr 8 1998

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irinotecan
9-aminocamptothecin
Cerebrospinal fluid
Pharmacokinetics
Primates
Cerebrospinal Fluid
Lactones
Plasmas
Area Under Curve

Keywords

  • 9-Aminocamptothecin
  • CSF penetration
  • Irinotecan
  • Topotecan

ASJC Scopus subject areas

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

Cite this

Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. / Blaney, Susan M.; Takimoto, Chris; Murry, Daryl J.; Kuttesch, Nancy; McCully, Cynthia; Cole, Diane E.; Godwin, Karen; Balis, Frank M.

In: Cancer Chemotherapy and Pharmacology, Vol. 41, No. 6, 08.04.1998, p. 464-468.

Research output: Contribution to journalArticle

Blaney, Susan M. ; Takimoto, Chris ; Murry, Daryl J. ; Kuttesch, Nancy ; McCully, Cynthia ; Cole, Diane E. ; Godwin, Karen ; Balis, Frank M. / Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. In: Cancer Chemotherapy and Pharmacology. 1998 ; Vol. 41, No. 6. pp. 464-468.
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abstract = "Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 1/kg per h, a volume of distribution at steady state (Vd(ss)) of 1.6 ± 0.7 l/kg and a half-life (t( 1/4 )) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7{\%} of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC(P)) was only 3.5 ± 2.1{\%}. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vd(ss) was 7.1 ± 1.3 l/kg, and the t( 1/4 ) was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0{\%} to 2.4{\%} of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5{\%} of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6{\%} of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 ± 3{\%}. SN-38 lactone and carboxylate could not be measured (<1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be 18{\%}. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32{\%}.",
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T1 - Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates

AU - Blaney, Susan M.

AU - Takimoto, Chris

AU - Murry, Daryl J.

AU - Kuttesch, Nancy

AU - McCully, Cynthia

AU - Cole, Diane E.

AU - Godwin, Karen

AU - Balis, Frank M.

PY - 1998/4/8

Y1 - 1998/4/8

N2 - Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 1/kg per h, a volume of distribution at steady state (Vd(ss)) of 1.6 ± 0.7 l/kg and a half-life (t( 1/4 )) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC(P)) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vd(ss) was 7.1 ± 1.3 l/kg, and the t( 1/4 ) was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be 18%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.

AB - Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 1/kg per h, a volume of distribution at steady state (Vd(ss)) of 1.6 ± 0.7 l/kg and a half-life (t( 1/4 )) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC(P)) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vd(ss) was 7.1 ± 1.3 l/kg, and the t( 1/4 ) was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be 18%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.

KW - 9-Aminocamptothecin

KW - CSF penetration

KW - Irinotecan

KW - Topotecan

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