Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 3, pp 621–627 | Cite as

Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats

  • María Isabel Mas-Fuster
  • Amelia Ramon-Lopez
  • Javier Lacueva
  • Antonio Compañ
  • Patricio Más-Serrano
  • Ricardo Nalda-Molina
Short Communication



In peritoneal metastasis condition, the fact that most of the disease is limited to the peritoneal cavity laid the foundations for a surgical treatment, including intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of this study was to evaluate the impact of the surgical procedures implied in open HIPEC technique, referred to laparotomy procedures followed by an intraperitoneal hyperthermic instillation (LIHI) on oxaliplatin tissue distribution and elimination. To delimit the influence of this procedure alone, oxaliplatin was administered as an intravenous (iv) bolus in both groups.


An experimental model in Wistar rats was employed, and LIHI was evaluated as a dichotomous covariate by using a population pharmacokinetic (PK) approach. Rats were randomized in two groups receiving 1.5 mg iv oxaliplatin alone or 1.5 mg iv oxaliplatin under LIHI conditions, carrying out a hyperthermic 5% dextrose instillation. The oxaliplatin plasma concentrations were characterized by an open two-compartment PK model.


Results concluded that surgical conditions affect the oxaliplatin elimination and distribution from blood to peripheral tissues, increasing the systemic drug exposure. Concretely, oxaliplatin peripheral volume of distribution, and clearance decreased by 48.6% and 55.3%, respectively, compared to the control group that resulted in a two-fold increase of the area under the concentration time curve.


Comparison in clinical practice of oxaliplatin PK parameters obtained after iv administrations with those obtained after HIPEC interventions must be done carefully. This would limit the use of iv PK parameters to simulate new scenarios for oxaliplatin in HIPEC.


Population pharmacokinetics Oxaliplatin Hyperthermia Intraperitoneal chemotherapy Peritoneal metastasis 



Hyperthermic intraperitoneal chemotherapy


Peritoneal metastasis




Laparotomy + intraperitoneal hyperthermic instillation



\(AU{{C}_{pla~0-\infty }}\)

Area under the plasma concentration time curve from time zero to infinite




Central volume of distribution


Intercompartmental clearance


Peripheral volume of distribution


Interindividual variability


Coefficient of variation


Goodness of fit plots


Normalized prediction distribution errors


Objective function value


Nonparametric bootstrap


Prediction-corrected visual predictive check


Confidence intervals


Standard deviation


Relative standard errors



The authors would like to acknowledge the Animal Experimentation Service of San Juan de Alicante, UMH, for all the assistance received.


This study was funded by the Fundación Navarro Tripodi and from Proyecto Bancaja-UMH. The funding sources had no involvement in study design, collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Research involving animals

Development of experimental model was held at the Animal Experimentation Service of San Juan de Alicante, attached to Miguel Hernández University of Elche (UMH). At the end of the procedure, rats were sacrificed. Care of the animals and drug administration were performed under veterinary control according to European Union Directive 2010/63/EU for animal experiments and with approval from the Ethics Committee of the UMH.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • María Isabel Mas-Fuster
    • 1
  • Amelia Ramon-Lopez
    • 1
  • Javier Lacueva
    • 2
  • Antonio Compañ
    • 2
  • Patricio Más-Serrano
    • 1
    • 3
  • Ricardo Nalda-Molina
    • 1
  1. 1.Division of Pharmacy and Pharmaceutics, Department of EngineeringSchool of Pharmacy, Miguel Hernández UniversityAlicanteSpain
  2. 2.Department of Pathology and SurgerySchool of Medicine, Miguel Hernández UniversityAlicanteSpain
  3. 3.Clinical Pharmacokinetics Unit, Pharmacy DepartmentHospital General Universitario de AlicanteAlicanteSpain

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