Population pharmacokinetics of oxaliplatin after intraperitoneal administration with hyperthermia in Wistar rats.

BACKGROUND: The evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. METHODS: Oxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3®. RESULTS: Intraperitoneal (n = 115) and plasma (n = 263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. CONCLUSIONS: This study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges.

OBJECTIVES: To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. PATIENTS AND METHODS: Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k(CSF) (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated. RESULTS: The mean estimates of the parameters were k(CSF)= 0.105 h(-1) and PC= 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3 × 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values. CONCLUSIONS: The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.

Kinetic modeling of triamterene intestinal absorption and its inhibition by folic acid and methotrexate.

The aim of this work was to study the intestinal absorption process of triamterene in situ in rats in order to gain insight on its absorption mechanism. The study shows an example of application of a pharmacokinetic model for drug disappearance from a compartment by simultaneous first order and Michaelis-Menten processes to the intestinal drug disappearance by absorption in a non-steady state system. The parameter used to quantify absorption was the absorption rate constant, determined in situ by means of a loop perfusion technique, performed in colon and in whole small intestine of rat at three pHs (5.00, 7.00 and 8.00) and in the presence of folic acid and methotrexate. Different concentrations of the drug were perfused in each condition. The concentrations versus time data were modeled with different kinetic absorption and inhibition differential equations to obtain the passive and active transport components and to elucidate the inhibition mechanisms. The results obtained confirm that triamterene is absorbed by means of passive diffusion and by a transporter or transporters related to folates. Folic acid and methotrexate are able to inhibit triamterene absorption. The results do not allow the selection of a competitive or non-competitive model for inhibition and this fact could be due to the presence of different carriers. The possibility of the existence of a secretion process sensitive to verapamil is also discussed.

Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies.

The influence of the secretion process on the absorption of ciprofloxacin, grepafloxacin and sparfloxacin has been evaluated by means of inhibition studies. Two well known P-glycoprotein inhibitors (cyclosporine, verapamil), a mixed inhibitor of P-glycoprotein and the organic cation transporter OCT1 (quinidine) and a well established MRP substrate (p-aminohipuric acid) have been selected in order to distinguish the possible carriers implicated. An in situ rat gut perfusion model and CACO-2 permeability studies are used. Both methods suggest the involvement of several types of efflux transporters for every fluoroquinolone. The relevance of the secretory pathway depends on the intrinsic permeability of the quinolone. The in vitro model seems to be more suitable for discriminating mechanisms underlying the absorption process, while in situ studies are less sensitive to inhibition studies.

QSAR analysis of hypoglycemic agents using the topological indices.

The molecular topology model and discriminant analysis have been applied to the prediction of some pharmacological properties of hypoglycemic drugs using multiple regression equations with their statistical parameters. Regression analysis showed that the molecular topology model predicts these properties. The corresponding stability (cross-validation) studies performed on the selected prediction models confirmed the goodness of the fits. The method used for hypoglycemic activity selection was a linear discriminant analysis (LDA). We make use of the pharmacological distribution diagrams (PDDs) as a visualizing technique for the identification and selection of new hypoglycemic agents, and we tested on rats the predictive ability of the model.