Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats.
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.
Division of Pharmacy and Pharmaceutics, Department of Engineering, School of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.
María Isabel
MI
Mas-Fuster
Division of Pharmacy and Pharmaceutics, Department of Engineering, School of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain. aramon@umh.es.
Amelia
A
Ramon-Lopez
Department of Pathology and Surgery, School of Medicine, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.
Javier
J
Lacueva
Department of Pathology and Surgery, School of Medicine, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.
Antonio
A
Compañ
Division of Pharmacy and Pharmaceutics, Department of Engineering, School of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.|Clinical Pharmacokinetics Unit, Pharmacy Department, Hospital General Universitario de Alicante, Alicante, Spain.
Patricio
P
Más-Serrano
Division of Pharmacy and Pharmaceutics, Department of Engineering, School of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.
Ricardo
R
Nalda-Molina
D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006979:Hyperthermia, Induced; D007274:Injections, Intraperitoneal; D007813:Laparotomy / Q000379:methods*; D008297:Male; D015233:Models, Statistical; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
Hyperthermia; Intraperitoneal chemotherapy; Oxaliplatin; Peritoneal metastasis; Population pharmacokinetics