Pharmacokinetics of gemcitabine in tumor and non-tumor extracellular fluid of brain: an in vivo assessment in rats employing intracerebral microdialysis.

PURPOSE: Gemcitabine is a pyrimidine nucleoside analogue anticancer agent that has shown promising anti-tumor activity in several experimental models of brain tumor. However, the pharmacokinetic behavior of gemcitabine in the central nervous system, especially in brain tumors is currently not well understood. In this study we evaluated the gemcitabine brain extracellular fluid (ECF) in normal rats and in ECF obtained from tumor- and tumor-free regions of glioma-bearing rats, to better understand the availability of the drug to brain and brain tumors. METHODS: The brain ECF pharmacokinetics of gemcitabine were investigated employing intracerebral microdialysis following intravenous administration of 10, 25 and 100 mg/kg doses in male Sprague-Dawley rats. In the second phase of the study, gemcitabine (25 mg/kg) was intravenously administered in rats implanted with C6 gliomas and ECF samples were simultaneously obtained from the tumor and tumor-free regions of the brain. Serial blood samples were obtained for evaluating the plasma pharmacokinetics of gemcitabine. Non-compartmental approach was employed for the analyses of the brain ECF and plasma pharmacokinetics of gemcitabine. RESULTS: Following intravenous administration, gemcitabine rapidly distributed into rat brain. At doses equivalent to 10, 25 and 100 mg/kg, the brain ECF gemcitabine AUC (area under the plasma concentration--time curve measured over the last sampling time point) values were 2.46 +/- 0.7, 3.20 +/- 1.1, and 9.06 +/- 3.0 microg h/ml, respectively. The brain ECF concentrations of gemcitabine declined in parallel with plasma concentrations. At the three doses evaluated, the relative brain distribution coefficient (AUC brainECF/AUC plasma) of gemcitabine ranged from 0.07 to 0.09 suggesting limited gemcitabine availability to brain tissues. Studies on C6 glioma-bearing rats revealed that following an intravenous dose of 25 mg/kg, the AUC values in the tumor-free and tumor-brain regions were 4.52 +/- 2.4, and 9.82 +/- 3.3 microg h/ml, respectively. Thus, the AUC of gemcitabine in the tumor ECF was on average 2.2-fold greater than the corresponding value in the tumor-free ECF of the brain. Plasma pharmacokinetics of gemcitabine remained unaltered in tumor-bearing animals, when compared to plasma pharmacokinetics in healthy animals. CONCLUSIONS: Our findings suggest that the overall brain exposure to gemcitabine is likely to be low as evident from the relative brain distribution coefficient of <0.1. However, the exposure is likely to be considerably higher in the brain tumor relative to tumor-free regions of the brain. The higher drug levels in brain tumor compared to the non-tumor region may facilitate selectively higher cytotoxicity against brain tumor cells.

Methylphenidate and cocaine: a placebo-controlled drug interaction study.

Up to thirty percent of cocaine addicted individuals may meet diagnostic criteria for Attention-Deficit/Hyperactivity Disorder (ADHD). Methylphenidate (MPH) is a highly effective and commonly used treatment for ADHD but, like cocaine, is a cardiovascular and central nervous system stimulant with the potential to cause toxicity at high doses. The present study was undertaken to investigate the likelihood of a toxic reaction in individuals who use cocaine while concurrently taking MPH. Seven non-treatment seeking cocaine-dependent individuals completed this placebo-controlled, crossover study with two factors: Medication (placebo, 60 mg MPH, 90 mg MPH) and Infusion (saline, 20 mg cocaine, 40 mg cocaine). Physiological measures included vital signs, adverse events, and electrocardiogram. Subjective response was measured with visual analog scale (VAS) ratings of craving and drug effect. Cocaine pharmacokinetic parameters were calculated for each participant at each drug combination, using a non-compartmental model. MPH was well tolerated, did not have a clinically significant impact on cocaine's physiological effects, and decreased some of the positive subjective effects of cocaine. MPH did not significantly alter the pharmacokinetics of cocaine. The study results suggest that MPH at the doses studied can likely be used safely in an outpatient setting with active cocaine users.

Induction of olfactory mucosal and liver metabolism of lidocaine by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Formulation of drugs for administration via the nasal cavity is becoming increasingly common. It is of potential clinical relevance to determine whether intranasal drug administration itself, or exposure to other xenobiotics, can modulate the levels and/or activity of nasal mucosal metabolic enzymes, thereby affecting the metabolism and disposition of the drug. In these studies, we examined changes in several of the major metabolic enzymes in nasal epithelial tissues upon exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as the impact of these changes on the metabolism of a model intranasally administered drug, lidocaine. Results of these studies show that TCDD can induce multiple metabolic enzymes in the olfactory mucosa and that the pattern of induction in the olfactory mucosa does not necessarily parallel that which occurs in the liver. Further, increases in enzyme levels noted by Western blot analysis were associated with increased activities of several nasal mucosal enzymes as well as with enhanced conversion of lidocaine to its major metabolite, monoethyl glycine xylidide (MEGX). These results demonstrate that environmental exposures can influence the levels and activity of nasal mucosal enzymes and impact the pharmacology of drugs administered via the nasal route.