Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients

Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency. © 1999 Cancer Research Campaig

Increased plasma carnitine concentrations in preeclampsia

OBJECTIVE: Preeclampsia is associated with abnormal lipid metabolism, including fatty acid metabolism. Carnitine plays an indispensable role in the oxidation of fatty acids. The aim of the study was to evaluate the possible role of abnormal fatty add oxidation in preeclampsia by comparing plasma carnitine levels between preeclamptic and healthy control pregnant women.METHODS: Plasma concentrations of free carnitine and short-, medium-, and long-chain acylcarnitines were investigated with electrospray tandem mass spectrometry in pregnant women with preeclampsia (n = 33) and in normotensive healthy pregnant control subjects (n = 28). Excluded were multiple pregnancies and women with preexistent hypertension, diabetes, renal dysfunction, immune disease, and intrauterine fetal death. Control subjects were healthy pregnant women without hypertension or proteinuria.RESULTS: The results revealed that, except for the medium-chain plasma acylcarnitines, all plasma carnitines were significantly increased (P &lt;.001) in the preeclamptic group (t test for impaired samples). Free carnitine and the short- and long-chain acylcarnitine values were increased by approximately 50% compared with the control group. Total and short-chain plasma acylcarnitine levels were significantly correlated to diastolic blood pressure, whereas no relationship could be demonstrated between carnitine concentrations and the variables proteinuria and systolic blood pressure.CONCLUSION: The considerable increased plasma carnitine concentrations, together with the accumulation of lipids, support the role of abnormal lipid metabolism in the pathophysiology of preeclampsia. It is suggested that toxic metabolites resulting from abnormal fatty acid oxidation in the placenta contribute to the endothelial dysfunction of preeclampsia. ( (C) 2004 by The American College of Obstetricians and Gynecologists.).</p

PHARMACOKINETICS OF BOLUS 5-FLUOROURACIL: RELATIONSHIP BETWEEN DOSE, PLASMA CONCENTRATIONS, AREA-UNDER-THE-CURVE AND TOXICITY.

Pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analysed until 24 hr after administration. The area under the concentration time curve from 0-90 min (AUC0-90) strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC30-240 and to that of AUC0-90 (r2= 0.970). Use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC0-90 at 353 mg/m2 was higher than the normal AUC0-90 for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer