A prospective study to assess the association between genotype, phenotype and Prakriti in individuals on phenytoin monotherapy

Abstract

BackgroundGenetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabolizing capacity and a unique phenotype to an individual. Phenytoin has large inter-individual variability in metabolism due to polymorphisms in CYP2C9 and CYP2C19. As per Ayurveda, Prakriti imparts a unique phenotype to an individual.ObjectiveTo assess whether Prakriti can substitute phenotyping [therapeutic drug monitoring (TDM)] and genotyping in individualizing therapy with phenytoin in epilepsy patients.Methods and materialsThis was a cross-sectional study conducted over a period of three years. Prakriti was assessed using standardized and validated software. Polymorphisms in CYP2C9 and CYP2C19 were assessed using Polymerase Chain Reaction (PCR)-Restriction fragment length polymorphism (PCR-RFLP). Plasma concentrations of phenytoin (phenotype) were determined using reverse phase-high performance liquid chromatography (RF-HPLC).ResultsTotal 351 patients were enrolled for the study. Kapha vata (KV) (39%) was the predominantly observed Prakriti followed by vata kapha (VK) (20.8%) and vata pitta (VP) (8.83%) among the patients. The CYP2C9 and CYP2C19 genotype distributions were in accordance with Hardy–Weinberg equilibrium. There was no association between Prakriti and genotypes and Prakriti and phenotype (p > 0.05 each). Patients with CYP2C9 *1/*3 genotype were thrice more likely to have toxic plasma concentrations of phenytoin as compared to those with wild-type genotype (*1/*1) (Adjusted odds ratio – 3.36; 95% C.I. 1.61, 7.01). However, no such association was observed between polymorphisms of CYP2C19 and phenotype.ConclusionsWe did not find any association between Prakriti and either phenotype or genotypes suggesting that Prakriti assessment would be of limited utility in individualizing phenytoin therapy in epilepsy patients.

Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region

“…1 . Of the 30 articles screened for eligibility, ten were excluded for subjects not originating from the MENA region [ 17 – 26 ], seven were excluded for phenytoin concentrations not being assessed [ 27 – 33 ], five were excluded for both subjects not originating from the MENA region and phenytoin concentrations not being assessed [ 34 – 38 ], one was excluded for genetic polymorphisms not being assessed [ 39 ], and two were excluded for being poster abstracts [ 40 , 41 ]. Between the five included studies , CYP2C9*1, *2, and *3; CYP2C19*1, *2, and *3; and multidrug resistance protein 1 [ MDR1 , also known as ATP-binding cassette sub-family B member 1 (ABCB1)] C3435T polymorphisms were evaluated.…”

“…Recognizing and understanding factors that contribute to interpatient variability in pharmacokinetics, pharmacodynamics, and associated clinical outcomes is essential to providing patient-individualized pharmacotherapy and disease management. In the management of epilepsy and seizure disorders, the significant role of genetic polymorphisms as one such factor has received increasing recognition, with phenytoin being an antiepileptic drug of particular interest, owing to its unique pharmacokinetic and pharmacodynamic profile [ 5 , 6 , 17 – 26 , 35 , 38 – 46 , 127 , 133 , 134 ]…”

In Vitro Therapeutic Equivalence of Two Multisource (Generic) Formulations of Sodium Phenytoin (100 mg) Available in Peru

“…Bioavailability and bioequivalence studies should be carried out in drugs with a narrow therapeutic range, such as phenytoin, which has a minimum effective concentration of 10 mg/L and an effective maximum of 20 mg/L (43)(44)(45). In this sense, a poor solution or a small change in the dose would lead to changes in bioavailability and plasma levels (46).…”

“…In this sense, a poor solution or a small change in the dose would lead to changes in bioavailability and plasma levels (46). At the same time, because these types of drugs form strong bonds with plasma proteins (i.e., albumin), they are displaced from binding with usual proteins by drugs that have a higher affinity for those proteins, which generates toxicity when the maximum concentration is exceeded (45). It is also known that phenytoin is metabolized by CYP2C9, and patients who are slow metabolizers are more likely to have toxicity (47).…”

Proton pump inhibitors in Iranian population: from clinical regimens to pharmacogenomics

“…The guidelines proposed by the International Conference on Harmonization (1998), suggest the presence of several factors associated with a drug pharmacokinetic to be ethnically sensitive (Committee, 1998;Noubarani et al, 2012). There are large number of reports in the literature speculating the ability of genotyping as an essential tool for safe and wise drug prescribing (Azarpira et al, 2010;Thaker et al, 2017;Vogl et al, 2015). A well-known polymorphism that affect drug metabolism involve oxidation by cytochrome P450 enzymes (CYP).…”