Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls

A COMPARATIVE STUDY OF THE EFFECT OF CARBAMAZEPINE AND VALPROIC ACID ON THE PHARMACOKINETICS AND METABOLIC PROFILE OF TOPIRAMATE AT STEADY STATE IN PATIENTS WITH EPILEPSY

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p <0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were several fold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles

A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles

Clinically relevant drug interactions with antiepileptic drugs

Some patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will receive, at some time in their lives, other medications for the management of associated conditions. In these situations, clinically important drug interactions may occur. Carbamazepine, phenytoin, phenobarbital and primidone induce many cytochrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes. Examples of agents whose serum levels are decreased markedly by enzyme-inducing AEDs, include lamotrigine, tiagabine, several steroidal drugs, cyclosporin A, oral anticoagulants and many cardiovascular, antineoplastic and psychotropic drugs. Valproic acid is not enzyme inducer, but it may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most notably phenobarbital and lamotrigine. Compared with older generation agents, most of the recently developed AEDs are less likely to induce or inhibit the activity of CYP or GT enzymes. However, they may be a target for metabolically mediated drug interactions, and oxcarbazepine, lamotrigine, felbamate and, at high dosages, topiramate may stimulate the metabolism of oral contraceptive steroids. Levetiracetam, gabapentin and pregabalin have not been reported to cause or be a target for clinically relevant pharmacokinetic drug interactions. Pharmacodynamic interactions involving AEDs have not been well characterized, but their understanding is important for a more rational approach to combination therapy. In particular, neurotoxic effects appear to be more likely with coprescription of AEDs sharing the same primary mechanism of action