Effects of etoricoxib on the pharmacokinetics of phenytoin (original) (raw)
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Pakistan journal of pharmaceutical sciences, 2018
The narrow therapeutic index, non-linear pharmacokinetics and unpredictable absorption require regular therapeutic monitoring of phenytoin. The influence of genetic differences, sex, age and race on the phenytoin plasma levels and its metabolites is well recognized. This study is aimed at evaluating phenytoin plasma drug concentration and its relationship with clinical response, persistent seizures and toxicity in different gender and various age groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of phenytoin in various sub-groups of epileptic patients for enhancing the safety, efficacy and minimizing the toxicity of phenytoin. A total of 48 plasma samples of epileptic patients for measuring the plasma phenytoin concentration were received. Only patients displaying persistent seizures or suspected of adverse effects were requested for drug monitoring. All these samples were analyzed for therapeutic drug monitoring with Enzyme-...
Effect of aceclofenac on pharmacokinetic of phenytoin
Pakistan journal of …, 2012
Abstract: Aceclofenac is presently most commonly prescribed analgesic for chronic pain and inflammatory conditions. In clinical practice, phenytoin and aceclofenac are used in a chronic condition of generalized seizure with concomitant chronic pain. Hence there are ...
Pharmaceuticals (Basel, Switzerland), 2017
Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p...
Frontiers in Veterinary Science
Drug-resistant epilepsy is a common complaint in dogs and affects up to 30% of dogs with idiopathic epilepsy. Experimental data suggest that targeting cyclooxygenase-2 (COX-2) mediated signaling might limit excessive excitability and prevent ictogenesis. Moreover, the role of COX-2 signaling in the seizure-associated induction of P-glycoprotein has been described. Thus, targeting this pathway may improve seizure control based on disease-modifying effects as well as enhancement of brain access and efficacy of the co-administered antiseizure medication. The present open-label non-controlled pilot study investigated the efficacy and tolerability of a COX-2 inhibitor (firocoxib) add-on therapy in a translational natural occurring chronic epilepsy animal model (client-owned dogs with phenobarbital-resistant idiopathic epilepsy). The study cohort was characterized by frequent tonic–clonic seizures and cluster seizures despite adequate phenobarbital treatment. Enrolled dogs (n = 17) receiv...
Neuropharmacology, 2010
Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures.
Phenytoin metabolic ratio: a putative marker of CYP2C9 activity in vivo
Pharmacogenetics, 2001
CYP2C9 mediates the oxidative metabolism of approximately 10% of drugs, some of which are characterized by a narrow therapeutic index. We aimed to validate genotype method and phenotype methodology, for evaluation of CYP2C9 activity in vivo. Thirty-one healthy subjects (22 male) received a single 300 mg dose of phenytoin. Blood was drawn periodically and urine was collected at intervals for 96 h. Plasma phenytoin and 5-(4-hydroxyphenyl)-5phenylhydantoin (p-HPPH) and urine S and R enantiomers of p-HPPH were determined by high-performance liquid chromatography. CYP2C9 genotyping was obtained by polymerase chain reaction followed by digestion with Sau96I and StyI for the identi®cation of CYP2C9 Ã 2 and CYP2C9 Ã 3, respectively. Eighteen subjects were CYP2C9 Ã 1 homozygous, seven were CYP2C9 Ã 2 heterozygous, four were CYP2C9 Ã 3 heterozygous, one was CYP2C9 Ã 2 homozygous and one was compound CYP2C9 Ã 2/CYP2C9 Ã 3 heterozygous. The allele frequencies of CYP2C9 Ã 1, CYP2C9 Ã 2 and CYP2C9 Ã 3 were 0.76 [95% con®dence interval (CI) 0.73±0.79], 0.16 (95% CI 0.13±0.19) and 0.08 (95% CI 0.05±0.11), respectively. The CYP2C9-mediated production of (S)-p-HPPH represented the major metabolic pathway of phenytoin biotransformation as its excretion accounted for 95.6 + 0.9% of`total' p-HPPH excretion over the 96 h collection interval. Phenytoin metabolic clearance to produce (S)-p-HPPH (PMC), correlated signi®cantly with (S)-p-HPPH (or`total' p-HPPH) content in 0±8, 0±12 and 0±24 urine collections (r 0.88, 0.85 and 0.89, respectively) and with phenytoin metabolic ratio (PMR) de®ned as the ratio of urine (S)-p-HPPH (or`total' p-HPPH) to mid-interval plasma phenytoin (r 0.90, 0.88 and 0.94, respectively). PMC and PMR exhibited a gene±dose effect so that the highest and lowest values were noted in homozygous subjects CYP2C9 Ã 1 and subjects carrying two defective alleles, respectively, whereas heterozygous subjects had intermediate values. CYP2C9 genotyping and several phenytoin metabolic indices are correlated with CYP2C9 activity in vivo. The utility of phenytoin to predict the metabolism of other CYP2C9 substrates justi®es further evaluation.
Active Pharmacovigilance in Epileptic Patients: A Deep Insight into Phenytoin Behaviour
Pharmacovigilance [Working Title]
Despite the introduction of new and more expensive anticonvulsant drugs, phenytoin (PHT) is still a first-line medication for common types of epilepsy such as tonic-clonic and complex partial seizures but not for absence seizures. PHT shows a nonlinear kinetics and a narrow therapeutic range, thus a fine balance must be found between efficacy and toxic effects. Since the free (unbound) drug is responsible for producing the pharmacological effect, the concentration in a novel biological fluid more closely related to arterial free plasma drug concentrationsaliva-is used in this study as part of the monitoring strategy. Therefore, in order to optimize therapy in epileptic patients under PHT treatment, plasma and saliva concentrations of PHT were measured, and adverse drug reactions were registered during a 2-year follow-up. CYP2C9, CYP2C19, and epoxide hydrolase polymorphisms (enzymes involved in PHT metabolism) were also analyzed using, in this way, pharmacogenetics for drug safety. The two PHT brands commercially available in our country and used in this study demonstrated similar pattern of efficacy and safety.
Macedonian Veterinary Review, 2023
The objective of this study was to examine the effect of ketoprofen with or without combination with xylazine on the level of cyclooxygenase-2 in mice. The intraperitoneal (i.p.) dose of ketoprofen and xylazine that caused an analgesic response in half of the mouse population was 1.26 mg/kg and 6.63 mg/kg, respectively. Serum cyclooxygenase-2 concentration (activity) in the control mice was 16.94 ng/ml. The ketoprofen-treated group (2.52 mg/kg, i.p.) decreased the cyclooxygenase-2 concentration by 58% (7.16 ng/ml). The combined ketoprofen and xylazine treatment (13.26 mg/kg, i.p.) decreased the cyclooxygenase-2 by 94% (0.98 ng/ml). The ketoprofen plasma concentration in the combined treatment group was significantly higher compared to the ketoprofen treatment group. Ketoprofen plasma concentrations measured at 0.25, 0.5, 1, 2, 4, and 24 hours were 19.07, 18.94, 14.66, 6.53, 5.44, and 5.54 μg/ml, respectively. Plasma concentrations of ketoprofen and xylazine were raised to 28.74, 29.74, 15.32, 13.04, 14.64, and 11.95 μg/ml or by 51%, 56%, 5%, 100%, 169%, and 116%, respectively. Ketoprofen pharmacokinetic variables were increased (AUC0-∞ (515%), AUMC0-∞ (2389%), MRT (305%), t1/2β (375%), Tmax (100%), and Cmax (55%)), while other values were decreased (Kel (79%), Vss (25%), and Cl (88%)). Our findings suggested a synergistic interaction between ketoprofen and xylazine on the level of cyclooxygenase-2 (pharmacodynamic interaction) which was exerted by modification of the ketoprofen pharmacokinetic properties in mice.
Journal of Pharmacology and Experimental Therapeutics, 2009
The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 genotype, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and Ϫ2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators. Phenytoin (PHT, 5,5-diphenylhydantoin) is among the most frequently prescribed antiepileptic drugs (AEDs). Among the older AEDs, the prevalence of use in the United States is: PHT Ͼ valproic acid Ͼ carbamazepine Ͼ phenobarbital (52, 19, 11, and 7%, respectively). The use of phenytoin is highest among the elderly population, those most likely to be taking other medications metabolized by CYP2C9. For example, it is estimated that 10.5% of nursing home residents had one or more AED orders, a prevalence 10 times greater than that found in the community (Garrard et al., 2007; Leppik, 2007). Although newer AEDs that may have fewer side effects have come on the market, PHT continues to occupy an important role in the pharmacological treatment of epilepsy, in particular, for patients