Plasma filtration for the controlled removal of liposomal therapeutics - From the apheretic site of view.

INTRODUCTION: Nanoparticle-based drug delivery systems can overcome the dose-limited toxicity of cytostatics. Pegylated doxorubicin-containing liposomes (PLD) are able to reduce cardiotoxicity. PLD quickly (in 2 days) attains therapeutic concentration in tumorous tissue (kinetic targeting), while its distribution in normal tissue, which is a cause of mucocutaneous toxicity (MCT), is delayed. We examined PLD extracorporeal removal effectivity, using plasma filtration (PF) to determine whether the drug could be withheld prior to its organ distribution responsible for MCT toxicity. METHODS: Nine patients suffering from platinum-resistant ovarian cancer were treated with a infusion of 50 mg/m2 of PLD/cycle - for four cycles q4w. Over 44 (46)-47 (49) hours postinfusion, the patients (14 cycles in total) underwent PF using the cascade method. Doxorubicin blood concentration was monitored by the HPLC method during 116 h. Individual pharmacokinetic parameters of doxorubicin were estimated. RESULTS: Over 44 (46)-47 (49) hours postinfusion, a single one-volume plasma filtration removed 35 (22-45) % of the remaining doxorubicin amount in the body. Symptoms of MCT - PPE-like syndrome (grade 3) appeared in one patient. Only one adverse reaction (1/14-7%) - short-term malaise and nausea - was reported as being related to PF. CONCLUSION: PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach, which can be a useful tool for the increased efficacy and tolerability of therapy with PLD. There were no serious signs of drug toxicity and/or PF-related adverse events.

Tissue and plasma concentrations of cephuroxime during cardiac surgery in cardiopulmonary bypass--a microdialysis study.

AIM: Wound and mediastinal infections are still very serious complications of open-heart surgery, in spite of the use of prophylactic antibiotics. The use of cardiopulmonary bypass (CPB) is associated with profound physiological changes affecting the pharmacokinetic behaviour of antibiotics. The aim of this pilot study was to monitor the tissue concentrations of cephuroxime (prophylactic antibiotic) in skeletal muscle during cardiac surgery using CPB by interstitial microdialysis. These concentrations were compared with plasma concentrations of cephuroxime. MATERIAL AND METHODS: Nine adult patients operated on using CPB were enrolled in this study. Cephuroxime was used as a prophylactic antibiotic (1st dose - 3 g of cefuroxime i.v. with anesthesia induction, 2nd dose - 1.5 g i.v. after CPB with protamine sulphate, 3rd dose - 1.5 g i.v. 8 hours after the surgery). Interstitial microdialysis was performed by probe CMA 60 (CMA Microdialysis AB, Sweden) inserted into the patient's deltoid muscle. Concentrations of cephuroxime in dialysates and in plasma were determined by the modified fluid chromatography method. The unbound cephuroxime fraction in plasma was obtained by using an ultrafiltration method. Samples of dialysates were collected at the following intervals: before CPB, each 30 minutes of CPB, at the end of CPB. Samples of blood were collected at these intervals: incision, start of CPB, each 30 minutes of CPB, at the end of CPB, at the end of surgery. Concentrations of cephuroxime in tissue were corrected by in vivo recoveries of the microdialysis probes. RESULTS: Plasma concentrations of cephuroxime were 163.5 +/- 40.1, 79.3 +/- 17.4, 73.7 +/- 16.8, 66.1 +/- 18.3, 57.0 +/- 10.9, 120.7 +/- 29.9 (mg L(-1)) and concentrations of free plasma fraction of cephuroxime were 119.5 +/- 35.2, 67.8 +/- 15.5, 66.0 +/- 12.5, 54.8 +/- 12.2, 49.6 +/- 9.8, 102.6 +/-26.0 (mg L(-1)). The concentrations of cephuroxime in dialysates were 44.3 +/- 15.7, 36.1 +/- 11.6, 31.9 +/- 9.3, 34.6 +/- 12.3, 27.6 +/-12.9, 56.7 +/- 17.6 (mg L(-1)). The mean in vivo recovery of cephuroxime in this study was 30%. Corrected concentrations (calculated by in vivo recovery) of cephuroxime in skeletal muscle were 148, 120, 106, 115, 92, 189 (mg L(-l)). CONCLUSION: Our preliminary results show that CPB can modify the time course of cephuroxime plasma and tissue concentrations. A decrease in plasma drug concentrations occurred at the start of CPB and lasted until CPB ended. An increase in plasma concentrations corresponds to the second drug dose after CPB. The concentrations of cephuroxime in skeletal muscle (corrected by recovery) during CPB are higher than plasma concentrations. It is influenced by important changes during CPB; closely associated with hemodilution, a shift of intravascular volume, solutes and albumin to the extravascular space and inconstant protein binding of cephuroxime during operation.

Influence of P-glycoprotein on the transplacental passage of cyclosporine.

The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P-glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno-fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L-[(3)H]-glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L-[(3)H]-glucose, passage across the placenta. Our findings indicate that P-glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier.

Influence of CYP3A metabolizer status on the pharmacokinetics and pharmacodynamics of amiodarone.

UNLABELLED: The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. METHODS: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6 beta-hydroxycortisol (6 beta-OHC and the ratio of 6 beta-hydroxycortisol to urinary free cortisol (6 beta-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 +/- 11 days (2nd period) and after 182 +/- 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 +/- 11 days (during the second period). RESULTS: Both the 6 beta-OHC excretion and 6 beta-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6 beta-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6 beta-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. CONCLUSION: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.