Bruno Lacarelle

Cerebrospinal Fluid Penetration and Pharmacokinetics of Vancomycin Administered by Continuous Infusion to Mechanically Ventilated Patients in an Intensive Care Unit

ABSTRACT Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher (P< 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.

Pharmacokinetics of Long-Term Propofol Infusion Used for Sedation in ICU Patients

The pharmacokinetics of propofol were determined in nine patients (seven men, two women, (mean +/- SD) 55.8 +/- 21.2 yr, 65.2 +/- 8 kg) requiring prolonged mechanical ventilation of their lungs. After an initial dose of 1-3 mg/kg, propofol was administered iv at 3 mg/kg/h for 72 h. Arterial blood samples were collected at selected times during and up to 72 h after infusion. Propofol whole blood concentrations were determined by high-performance liquid chromatography with fluorescence detection. Individual pharmacokinetic parameters were estimated by noncompartmental analysis. Derived pharmacokinetic parameters showed a long terminal phase (T1/2 = 1878 +/- 672 min), a large volume of distribution at steady state (Vdss = 1666 +/- 756 l), and a high total body clearance (Cl = 1.57 +/- 0.56 l/min). While the propofol terminal elimination half-life is longer than that previously reported, emergence from sedation after prolonged administration will be governed by both redistribution mechanisms arising from the large distribution volumes and elimination from the body.

Serum increases CYP1A1 induction by 3-methylcholanthrene

CYP1A1 is largely involved in carcinogenesis through the bioactivation of numerous procarcinogens. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) leads to induction of CYP1A1 via AhR pathway. We have previously demonstrated that fetal bovine serum (FBS) induces CYP1A1 gene transcription. In this work, we show evidence that the serum does not contain an AhR ligand and we evaluated the effect of a 3-methylcholanthrene (3-MC) and FBS cotreatment on CYP1A1 expression. CYP1A1 activity was potentiated by this treatment. This potentiation was at least in part associated with an increase of the CYP1A1 mRNA and gene transcription levels. FBS potentiation of CYP1A1 PAH-mediated induction was related to a significant increase of single strand breaks of DNA as compared to a single 3-MC treatment. Moreover, we demonstrated that human serum induces CYP1A1 with a high interindividual variability. The potentiation by serum of polycyclic aromatic hydrocarbon CYP1A1 induction could be involved in the etiology of some human cancers.