Phenytoin Co-administration Research Articles

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine.

AimsCarbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates.MethodsA combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11‐epoxide. Nonlinear mixed effects modelling was used to build a population‐PK model.ResultsIn total, 248 observations were collected from 80 subjects. A 1‐compartment PK model with first‐order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h−1. Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1‐416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11‐epoxide.ConclusionOur data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11‐epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

Oral phenytoin protects against experimental cyclophosphamide-chemotherapy induced hair loss

In the current study, effects of oral phenytoin on hair growth in cyclophosphamide-treated rats were assessed with the goal of evaluating the ability of phenytoin to suppress chemotherapy-induced hair loss. Thirty-six rats were randomly assigned to six groups (1k6) of six each (n=6). In all groups, anagen was induced in flank skin of rats by depilation. On day 9 (anagen VI), rats were injected once with either distilled water (groups 1–3) or cyclophoshamide (groups 4–6). From day 10, rats in group 1 and 4 received oral vehicle (distilled water), groups 2 and 5 received oral phenytoin (50mg/kg), while groups 3 and 6 also received oral phenytoin (100mg/kg). Drug or vehicle was administered daily for a period of 28days. The flank area was serially photographed. At the end of the experimental period, rats were sacrificed to correlate visible hair growth with a histological profile of follicle response and recovery. Glutathione (GSH), glutathione peroxidase (GPX) and lipid peroxidation status were assessed. Cyclophosphamide (CYP) treatment was associated with gross morphologic and histological evidence of hair loss in the flanks, microscopic evidence of hair-shaft thinning, increased skin lipid peroxidation, decreased GSH level, and reduction in GPX activities. Phenytoin co-administration was associated with evidence of improved hair growth, increased hair-shaft thickness, reduced skin lipid peroxidation, increased GSH level, and increased GPX activities. This study showed that oral phenytoin can suppress hair loss due to CYP therapy in rats; however, further studies are needed to evaluate its potential application in chemotherapy-induced alopecia.

Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy

PurposeValproic acid (VPA), which is widely used to treat epilepsy, migraine, and bipolar disorder, can causes severe hyperammonemia. However, the mechanism responsible for this adverse effect is not readily apparent. We previously reported that phenytoin coadministration is a strong risk factor for the development of hyperammonemia during VPA-based therapy. In this study, we focused on glutamine synthetase, which catalyzes the synthesis of glutamine from glutamate and ammonia and examined the association with the development of hyperammonemia during VPA-based therapy. MethodsFor this study, we recruited 202 Japanese pediatric patients having epilepsy. We selected three polymorphisms (rs10911070, rs10797771, and rs10911021) in the glutamine synthetase (GLUL) gene. Hyperammonemia was defined as a plasma ammonia level exceeding 200 or 170μg/dL. We evaluated the association between the development of hyperammonemia during VPA-based therapy and the patient characteristics, including three GLUL polymorphisms. ResultsThe number of patients who developed hyperammonemia during VPA-based therapy was 20 (9.9%) using the 200μg/dL cutoff value and 30 (14.9%) using the 170μg/dL cutoff value. Using a multivariate logistic regression analysis, the GLUL rs10797771 polymorphism and phenytoin coadministration in the 200μg/dL cutoff value, and female in addition to two factors in the 170μg/dL cutoff value, had significant associations with a plasma ammonia level elevation during VPA-based therapy. ConclusionPhenytoin coadministration, GLUL rs10797771 polymorphism in the 200μg/dL cutoff value, and female in addition to two factors in the 170μg/dL cutoff value, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy.

Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis

The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT). 476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined. Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p=0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p<0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p=0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p=0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol. This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol.

バルプロ酸服用中のてんかん患者における高アンモニア血症発生リスクに関する症例対照研究

Hyperammonemia is an adverse effect of valproic acid,though it is rarely associated with fatal encephalopathy or disturbance of consciousness.The purpose of this study was to investigate the clinical risk factors for hyperammonemia in patients with epilepsy undergoing valproic acid therapy.To do this,we conducted a survey retrospectively from January 2006 to June 2008.We also performed a case-control study in which blood ammonia levels and other data were measured in inpatients and outpatients,defining hyperammonemia as a blood ammonia level exceeding 200μg/dL.There were 90 cases and 450 controls.Multiple logistic regression analysis was also performed to investigate the risk factors for hyperammonemia,using the cases as a criterion variable.The explanatory variables were factors that showed significance (P<0.05)in univariate analysis.According to multiple regression analysis,risk factors for hyperammonemia were phenytoin coadministration (odds ratio (OR),5.89;95% confidence interval (CI),3.41 to 10.2;p<0.001),phenobarbital coadministration (OR,2.30;95% CI,1.28 to 4.11;p=0.005),and dose of valproic acid (per mg/kg/day,OR,1.05;95% CI,1.02 to 1.07;p<0.001).However,slow-release valproic acid formulations reduced the risk of hyperammonemia (OR,0.51;95% CI,0.30 to 0.85;p= 0.010).In conclusion,identification of risk factors for hyperammonemia due to valproic acid in epileptic patients can help minimize adverse effects.

Cyclosporin-phenytoin interaction: re-evaluation using metabolite data.

1 Freeman et al. (1984) evoked enzyme induction to explain the lower plasma concentration of cyclosporin following phenytoin co-administration in man. 2 We have examined the whole blood concentration data of two metabolites of cyclosporin, as well as unchanged drug, all measured by h.p.l.c., associated with the above mentioned study. 3 Phenytoin produced no significant effect on either the terminal half-life of both metabolites or the ratio of area under the concentration-time curve of metabolite to parent drug. 4 These data strongly suggest that phenytoin reduces the absorption of cyclosporin; they do not generally support the idea that phenytoin induces cyclosporin metabolism.