Agnès Tran

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: In vitro and in vivo comparison and calculation of in vivo inhibition constants

The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo.

IN VITRO AND IN VIVO INHIBITORY EFFECT OF STIRIPENTOL ON CLOBAZAM METABOLISM

A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate Ki and IC50 of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with Ki = 1.59 ± 0.07 and 0.516 ± 0.065 μM and IC50 = 1.58 μM [95% confidence interval (CI95%) = 1.20–2.08] and 3.29 μM (CI95% = 1.87–5.79), respectively. STP inhibited also more strongly the 4′-hydroxylation of NCLB to 4′-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with Ki = 0.139 ± 0.025 μM and IC50 = 0.276 μM (CI95% = 0.206–0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC50 = 0.023 μM (CI95% = 0.016–0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC50 = 2.99 μM (CI95% = 2.11–4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.

Mangafodipir prevents liver injury induced by acetaminophen in the mouse.

BACKGROUND/AIMS Acute liver failure (ALF), characterized by massive hepatocyte necrosis, is often caused by drug poisoning, particularly with acetaminophen (APAP). Hepatocyte necrosis is consecutive to glutathione depletion by NAPQI, a metabolite of APAP, and to mitochondrial damages caused by reactive oxygen species (ROS) overproduction. Considering the structure of Mangafodipir, a contrast agent currently used in magnetic resonance imaging of the liver, we hypothesized that this molecule could exert an antioxidant activity and be possibly used as a treatment of APAP-induced ALF. METHODS/RESULTS Mangafodipir is endowed with superoxide dismutase, catalase, and glutathione reductase activities. It can inhibit ROS production by hepatocytes in culture, and protect those cells from oxidative stresses induced by exposure to xanthine oxidase, H(2)O(2), or UV light. Moreover, preventive or curative administration of Mangafodipir to mice with APAP-induced ALF significantly increases survival rates, and abrogates aspartate aminotransferase elevation and histological damage. CONCLUSIONS Those data point out the potential interest of Mangafodipir in the treatment of toxic ALF in humans.

Pharmacokinetic‐pharmacodynamic study of oral lansoprazole in children

We investigated the pharmacokinetics, pharmacodynamics, and tolerability of lansoprazole in children after single and multiple administrations.

Oxcarbazepine Pharmacokinetics and Tolerability in Children With Inadequately Controlled Epilepsy

This two‐part, open‐label study evaluated the pharmacokinetics, safety, and tolerability of oxcarbazepine as combination therapy in 112 children 2 to 12 years old with inadequately controlled epilepsy. Part I was a pharmacokinetic study in children stratified by age (2–5 years and 6–12 years) and randomized to receive a single oxcarbazepine dose of 5 mg/kg or 15 mg/kg. Mean specific AUC and t1/2 values of the active metabolite (MHD) were approximately 30% lower in younger children compared with older children, regardless of dose. Part II was a 4‐month safety, tolerability, and pharmacokinetic study in which children received oxcarbazepine doses of 11 to 68 mg/kg/day. The mean specific oxcarbazepine daily dose was 38% higher in younger children compared with older children. Similarly, mean trough plasma MHD concentrations were 34% lower in younger children. Six (5%) children discontinued due to adverse events. Oxcarbazepine was safe and well tolerated. Younger children require higher oxcarbazepine doses because of rapid clearance.

Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design.

Stiripentol, a new antiepileptic drug inhibiting cytochrome P450-enzymes, suggested some efficacy when combined with carbamazepine in an open trial in refractory partial epilepsy of childhood. Our objective was to test these results in a placebo-controlled trial. To limit the number of patients included, we used an enrichment and withdrawal design. Among the 67 children entered in a 4-month open add-on stiripentol study following a 1-month single-blind placebo baseline, the 32 responders were randomized for 2 months either to continue stiripentol (n = 17) or to withdraw to placebo (n = 15). If seizures increased by at least 50% after randomization compared with baseline, the patients dropped out (primary end point): there were six patients on stiripentol and eight patients on placebo (not significant). However, a decrease in seizure frequency compared with baseline (secondary end point) was greater on stiripentol (—75%) than on placebo (—22%) (P< .025). Twelve patients experienced at least one adverse event on stiripentol (71%) compared with four patients on placebo (27%); none were reported as severe. The combination of stiripentol and carbamazepine proved to reduce seizure frequency in children with refractory partial epilepsy, although it failed to show a significant impact according to the escape criteria selected as the primary end point in the present study, for ethical reasons. (J Child Neurol 2006; 21: 496—502;

Pharmacogenomics of Fluorouracil, Irinotecan, and Oxaliplatin in Hepatic Metastases of Colorectal Cancer

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable inter-individual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.

Isoniazid pharmacokinetics in children according to acetylator phenotype

The pharmacokinetics of isoniazid (INH) was studied in children (0–196 months old) according to their acetylator phenotype, estimated from the metabolic acetyl INH/INH molar plasma concentration ratio (MR) measured 3 h after INH oral administration. There were 17 slow (MR < 0.48) and 17 fast acetylators (MR ≥ 0.48). The mean apparent plasma clearance was significantly lower, the mean apparent volume of distribution higher and the half‐life longer in the slow acetylator group (C1, 0.298 ± 0.099 L/h/kg; Vd, 1.56 ± 0.65 L/kg; t1/2, 3.88 ± 01.89 h) than in the fast acetylator group (Cl, 0.528 ± 0.234 L/h/kg; Vd, 1.06 ± 0.45; t1/2, 1.64 ± 1.1 h). The half‐life decreased with age.

Stiripentol (STP) in Childhood Partial Epilepsy: A Randomized Placebo-Controlled Trial With An Enrichment and Withdrawal Design

Clinical Pharmacology & Therapeutics (2003) 73, P43–P43; doi: