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Fulltext Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

Zhou Y, Nevosadová L, Eliasson E, Lauschke VM

Hum Genomics, 2023 Feb 28;17(1):15.
PMID: 36855170 DOI: 10.1186/s40246-023-00461-z

BACKGROUND: Genetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking.
RESULTS: Frequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs.
CONCLUSIONS: This study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

Matched MeSH terms: Phenytoin*
Pharmacokinetics of phenytoin in routine clinic patients in Malaysia

Ismail R, Rahman AF, Chand P

J Clin Pharm Ther, 1994 Aug;19(4):245-8.
PMID: 7989403

We estimated individual and population Michaelis-Menten pharmacokinetic parameters for phenytoin (DPH) in epileptic patients attending our neurology clinic using the computer programme. OPT. Our results agreed well with literature values but were lower than those we obtained earlier in a smaller number of patients. The Km was independent of age, weight and sex but there was a weak, correlation between Vm and body weight. We conclude that the use of population Vm and Km in normograms could lead to errors in DPH dose estimations as they correlated very poorly with patient characteristics. OPT was easy to use and sufficiently accurate for deriving dose estimates in routine patients. Its use would enable practitioners to generate their patients' own parameters for use in individual dosage adjustments. The estimates can subsequently be updated as more data become available.

Matched MeSH terms: Phenytoin/blood; Phenytoin/pharmacokinetics*; Phenytoin/pharmacology; Phenytoin/therapeutic use
Michaelis-Menten pharmacokinetics of phenytoin in adult Malaysian patients

Ismail R, Rahman AF

J Clin Pharm Ther, 1990 Dec;15(6):411-7.
PMID: 2089048

We reviewed our data from 122 records of patients taking phenytoin for the treatment of various types of epilepsy and selected 15 (age range 10-43 years old) who were on phenytoin alone to calculate Michaelis-Menten pharmacokinetic parameters. The average Vm and Km for this age group was found to be 8.45 mg/kg/day and 6.72 mg/litre, respectively. Km was independent of age and weight. Vm correlated well with weight but there was no relationship with age.

Matched MeSH terms: Phenytoin/pharmacokinetics*
Degradation of 5,5-diphenylhydantoin by chlorination and UV/chlorination: kinetics, transformation by-products, and toxicity assessment

Mansor NA, Tay KS

Environ Sci Pollut Res Int, 2017 Oct;24(28):22361-22370.
PMID: 28801887 DOI: 10.1007/s11356-017-9892-6

This study investigated the reaction kinetics and mechanism of the degradation of 5,5-diphenylhydantoin (DPH) during conventional chlorination and UV/chlorination. DPH is one of the antiepileptic drugs, which has frequently been detected in the aquatic environment. For chlorination, the second-order rate constant for the reaction between DPH and free active chlorine (FAC) was determined at pH 5 to 8. At pH 6 to 8, the efficiency of chlorination in the removal of DPH was found to be dominated by the reaction involving hypochlorous acid (HOCl). The result also showed that anionic species of DPH was more reactive toward FAC as compared with neutral DPH. For UV/chlorination, the effect of FAC dosage and pH on the degradation of DPH was evaluated. UV/chlorination is a more effective method for removing DPH as compared with conventional chlorination and UV irradiation. The DPH degradation rate was found to increase with increasing FAC concentration. On the other hand, the degradation of DPH was found to be more favorable under the acidic condition. Based on the identified transformation by-products, DPH was found to be degraded through the reaction at imidazolidine-2,4-dione moiety of DPH for both chlorination and UV/chlorination. Toxicity study on the chlorination and UV/chlorination-treated DPH solutions suggested that UV/chlorination is a more efficient method for reducing the toxicity of DPH.

Matched MeSH terms: Phenytoin/analysis*; Phenytoin/radiation effects; Phenytoin/toxicity
The complexity of achieving anticoagulation control in the face of warfarin-phenytoin interaction: an Asian case report

Hassan Y, Awaisu A, Aziz NA, Ismail O

Pharm World Sci, 2005 Feb;27(1):16-9.
PMID: 15861930

Phenytoin has been reported to have major interactions with warfarin. Phenytoin induces warfarin's metabolism. However, there are many case reports which provide conflicting conclusions. Here, we report a case of a 65-year-old man with mechanical heart valve on chronic warfarin therapy who experienced persistent fluctuations of INR and bleeding secondary to probable warfarin-phenytoin interactions. The patient's anticoagulation clinic visits prior to hospitalization were thoroughly evaluated and we continued to follow-up the case for 3 months post-hospitalization. The reported interaction could be reasonably explained from the chronology of events and the pattern of INR fluctuations whenever phenytoin was either added or discontinued from his drug regimen.

Matched MeSH terms: Phenytoin/adverse effects*; Phenytoin/therapeutic use
In Vitro Evaluation of Novel Phenytoin-Loaded Alkyd Nanoemulsions Designed for Application in Topical Wound Healing

Teo SY, Yew MY, Lee SY, Rathbone MJ, Gan SN, Coombes AGA

J Pharm Sci, 2017 01;106(1):377-384.
PMID: 27522920 DOI: 10.1016/j.xphs.2016.06.028

Phenytoin-loaded alkyd nanoemulsions were prepared spontaneously using the phase inversion method from a mixture of novel biosourced alkyds and Tween 80 surfactant. Exposure of human adult keratinocytes (HaCaT cells) for 48 h to alkyd nanoemulsions producing phenytoin concentrations of 3.125-200 μg/mL resulted in relative cell viability readings using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide of 100% confirming nontoxicity and suggesting cell proliferation activity. Phenytoin-loaded alkyd nanoemulsions generally resulted in higher mean cell viability compared with equivalent concentration of phenytoin solutions, suggesting that the nanoemulsions provided a controlled-release property that maintained the optimum phenytoin level for keratinocyte growth. HaCaT cell proliferation, measured by 5-bromo-2-deoxyuridine uptake, was found to increase following exposure to increasing phenytoin concentration from 25 to 50 μg/mL in solution or encapsulated in nanoemulsions but declined at a drug concentration of 100 μg/mL. An in vitro cell monolayer wound scratch assay revealed that phenytoin solution or nanoemulsions producing 50 μg/mL phenytoin concentration resulted in 75%-82% "scratch closure" after 36 h, similar to medium containing 10% fetal bovine serum as a cell growth promoter. These findings indicate that phenytoin-loaded alkyd nanoemulsions show potential for promoting topical wound healing through enhanced proliferation of epidermal cells.

Matched MeSH terms: Phenytoin/administration & dosage*; Phenytoin/pharmacology
Fulltext Cyclosporine-induced gingival overgrowth in a patient with hepatitis C virus infection - a case report

Subramaniam, U.

Malaysian Dental Journal, 2007;28(2):103-106.
MyJurnal

Gingival overgrowth is a well-recognized unwanted effect associated with three major drugs / drug groups - phenytoin, cyclosporine and the calcium channel blockers. Cyclosporine is the first-choice immunosuppressant for preventing allograft rejection in patients who have received organ or bone marrow transplants. This report aims to highlight a case in which the patient on cyclosporine therapy had also contracted Hepatitis C virus infection.

Matched MeSH terms: Phenytoin
Fulltext Phenytoin-induced severe thrombocytopaenia post dexamethasone co-administration in a patient with intracerebral haemorrhage

Lau, E.F., Mazlan, M., Shanmugam, H.

JUMMEC, 2018;21(2):31-34.
MyJurnal

Phenytoin is commonly prescribed for the prophylaxis of seizures in neurosurgical patients. A phenytoininduced
serious adverse effect of thrombocytopenia has been reported in the literature. The concurrent
use of dexamethasone, another commonly prescribed drug in neurosurgical patients, has been reported to
aggravate this adverse haematological effect. We present a report of phenytoin-induced thrombocytopenia
in a patient concurrently prescribed with dexamethasone, after an intracerebral haemorrhage secondary to
a rupture of an arteriovenous malformation. The thrombocytopenia was noted after two weeks of phenytoin
medication. Phenytoin was immediately withheld, and seven units of random donor platelets were transfused.
A gradual resolution of thrombocytopenia was observed within a week.

Matched MeSH terms: Phenytoin
Effect of fluoxetine on maximal electroshock seizures in mice: acute vs chronic administration

Raju SS, Noor AR, Gurthu S, Giriyappanavar CR, Acharya SB, Low HC, et al.

Pharmacol Res, 1999 Jun;39(6):451-4.
PMID: 10373242

There are no definite reports regarding the effects of chronic fluoxetine on animal models of epilepsy. Since chronically administered fluoxetine, in comparison to acutely administered fluoxetine has different effects on CNS, the present study was undertaken to investigate the effect of acute and chronic fluoxetine pretreatment, on a median anticonvulsant dose (ED50) of phenytoin in male ICR albino mice. Additionally, the effects of fluoxetine pretreatment on median convulsive current (CC50) in the presence and absence of phenytoin were investigated and results were compared. The maximal electroshock seizure (MES) test was used to estimate the ED50of phenytoin. The electroshock threshold test was used to estimate CC50. ED50and CC50values were calculated by probit analysis. The effects of the chronic and acute fluoxetine groups on the ED50of phenytoin were significantly different (P<0.05), and on CC50this difference was not statistically significant. Chronic fluoxetine insignificantly increased the ED50of phenytoin and decreased the CC50while acute fluoxetine decreased the ED50of phenytoin and increased the CC50. Our results indicate that chronic fluoxetine does not have an antiepileptic property and it may have dubious proconvulsant properties, contrary to acute fluoxetine.

Matched MeSH terms: Phenytoin/pharmacology
Effect of propranolol and nifedipine on maximal electroshock-induced seizures in mice: individually and in combination

Raju SS, Gopalakrishna HN, Venkatadri N

Pharmacol Res, 1998 Dec;38(6):449-52.
PMID: 9990653

A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kg-1 on maximal electroshock (MES)-induced seizure in mice was investigated. Propranolol in doses of 10 mg kg-1 and 20 mg kg-1, and nifedipine in doses of 8 mg kg-1 and 16 mg kg-1 significantly modified MES activity. Propranolol (40 mg kg-1), and a combination of propranolol (20 mg kg-1) and nifedipine (8 mg kg-1), produced antiMES activity, which was comparable to that of phenytoin (30 mg kg-1). In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios (F/E ratio) were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice.

Matched MeSH terms: Phenytoin/pharmacology*
Cerebral infarction in juvenile rheumatoid arthritis

Gururaj AK, Chand RP, Chuah SP

Clin Neurol Neurosurg, 1988;90(3):261-3.
PMID: 3197355

Cerebral involvement associated with juvenile rheumatoid arthritis is rare. It is not influenced by treatment and the presentation can be varied. We describe a case of cerebral infarction secondary to vasculitis in a child with juvenile rheumatoid arthritis.

Matched MeSH terms: Phenytoin/therapeutic use
Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC, et al.

JAMA, 2014 Aug 6;312(5):525-34.
PMID: 25096692 DOI: 10.1001/jama.2014.7859

The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown.

Matched MeSH terms: Phenytoin/adverse effects*; Phenytoin/pharmacokinetics
Fulltext Congenital renal anomalies - a dissection observational study

Bilodi, Arun Kumar .S, Gangadhar, M R

Malaysian Journal of Medical Research, 2017;1(1):14-18.
MyJurnal

Anomaly is a congenital disorder. It is a medical condition that is present since birth. But the word congenital neither applies nor excludes genetic disorder. Congenital anomalies due to environmental factors are called as Teratogens. Infections, deficiency in the diet and toxins are environmental causes. Maternal folic acid deficiency may cause spina bifida. Intake of alcohol, and certain prescribed drugs like phenytoin may cause congenital anomalies or defects. Apart from physical anomalies, other types of congenital disorders are inborn errors of metabolism (Kumar, Abbas and Fausto, 2005). About 15% to 25% of anomalies are due to chromosomal factors or single gene factors, 8% to 12% anomalies are said to be due to environmental factors, 25% are said to be due to multifactorial inheritance 40% to 60% of anomalies are of unknown origin (Stevenson, 1993 ; Nelson and Holmes, 1984). Congenital anomalies are present since birth with structural deformity found immediately after birth or their presence may be detected by signs and symptoms later on (Holland and Brew, 1991). Congenital Anomalies are seen in 2% of population as major abnormality. There are two types of abnormalities, namely malformations where growth disturbances occur during embryogenesis and the other is deformation. It is late change that appears in a structure which was normal earlier (Roizen and Patterson, 2003).

Matched MeSH terms: Phenytoin
Fulltext Evaluation of blood sampling times and indications for therapeutic drug monitoring services

Aishah Hamzah, Ab Fatah Ab Rahman

Malaysian Journal of Pharmaceutical Science, 2008;6(1):1-11.
MyJurnal

The appropriateness of sampling times and indications for monitoring of serum drug concentrations for the purpose of therapeutic drug monitoring (TDM) were evaluated at three hospitals on the east coast of Malaysia. Appropriateness criteria for indication and sampling were adapted from previously published criteria and with input from local TDM pharmacists. Six drugs were chosen, namely gentamicin, digoxin, carbamazepine, phenobarbital, phenytoin, and valproic acid. A total of 265 TDM requests were evaluated. Appropriateness of the indication for TDM ranged from 77.4% to 82%, while that for sampling ranged from 34.2% to 62.1%. There were no significant differences between the three hospitals in both categories of appropriateness. Among different drug groups, the percentage of appropriate indication was found to be highest with antiepileptic drugs. Antiepileptic drugs, however, had the lowest rate of appropriate sampling. Overall, findings from the three hospitals showed very encouraging results with almost 80% of the requests considered as appropriately indicated. However, the percentage of appropriateness of sampling was lower, and thus may require further investigation.

Matched MeSH terms: Phenytoin
Fulltext A painful gum

Loh KY, Kew ST

Aust Fam Physician, 2007 Sep;36(9):755.
PMID: 17885711

This middle aged Malaysian man presented complaining of painful gums for a few months. He is known to have had epilepsy since childhood.
Keywords: quiz; gum hypertrophy

Matched MeSH terms: Phenytoin/adverse effects
Fulltext Neurocysticercosis an uncommon intra-cerebral infection in Malaysia

Arasu K, Khairul A, Waran V

Med J Malaysia, 2005 Oct;60(4):514-6.
PMID: 16570721

Neurocysticercosis, infection of the central nervous system (CNS) by larvae of the pork tapeworm Taenia solium, is the commonest neuroparasitic infection in humans. However in countries as in Malaysia it poses a diagnostic problem as the disease in not seen amongst the local population; however with the arrival of immigrant workers, a number of cases have recently been diagnosed. There were 3 cases of neurocysticercosis reported in our centre over the last 5 years.

Matched MeSH terms: Phenytoin/therapeutic use
Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population

Chang CC, Ng CC, Too CL, Choon SE, Lee CK, Chung WH, et al.

Pharmacogenomics J, 2017 03;17(2):170-173.
PMID: 26927288 DOI: 10.1038/tpj.2016.10

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Matched MeSH terms: Phenytoin/adverse effects*
Fulltext An evaluation on pharmacokinetics parameters of phenytoin in adult epileptic patients: a single centre study from Malaysia

Tan, Kenny, Luen, Leong Wei, Ong, Yi Ping, Khai, H’ng Kee, Tan, Li May, Siti Nur Fatihah Abd Rahman, et al.

Malaysian Journal of Pharmaceutical Science, 2020;18(1):77-83.
MyJurnal

Phenytoin follows Michaelis-Menten, a non-linear pharmacokinetics that occurs when drug molecules saturates the enzymes ability to metabolise the drug. When this occurs, steady state phenytoin serum concentration increases in a disproportionate manner after a dosage increase. General population data are usually used for the phenytoin dose calculation. However, many studies show that population pharmacokinetic parameters of phenytoin have high variations. Thus, use of specific local pharmacokinetic parameters for each population group in estimating individualised phenytoin dose can reduce phenytoin toxicity cases. This prospective, observational study was conducted to estimate a local Vmax and Km of phenytoin for adult epileptic patients in neurological ward and clinic at Hospital Pulau Pinang, Malaysia. All therapeutic drug monitoring of oral capsule phenytoin were studied in a three-month data collection period. Out of the 17 subjects in our study, there are 13 male subjects (76.47%) and 4 female subjects (23.53%). A total 11 Malay subjects (64.71%), 4 Chinese subjects (23.53%) and 2 Indian subjects (11.76%) were included. Median Vmax and Km were found to be 8.25 mg/kg/day and 3.80 mg/l. Male subjects have a higher Vmax (8.30 mg/kg/day) but a lower Km (3.3 mg/l). Chinese population has the highest Vmax (8.80 mg/kg/day). For Km, Indian population is the highest, with a value of 5.5 mg/l. From our study, gender does not correlate with Vmax and Km of phenytoin (p-value > 0.05). Ethnicity was also found to have no association with Vmax and Km (p-value > 0.05). Local Vmax (8.25 mg/kg/day) is higher and Km (3.8 mg/l) is lower when compared with standard Vmax (7 mg/kg/day) and Km (4 mg/l) obtained from Caucasian population.

Matched MeSH terms: Phenytoin
Fulltext An update on HLA alleles as pharmacogenetic markers for antiepileptic drug-induced cutaneous adverse reaction

Then, Sue-Mian, Azman Ali Raymond

Neuroscience Research Notes, 2019;2(2):1-17.
MyJurnal

Epilepsy is a common neurological disorder affecting approximately 50 million people worldwide. Antiepileptic drugs (AEDs) are commonly used to treat the disease depending, mainlyon the type of seizure. However, the useof AEDs mayalso lead to cutaneous adverse drug reactions (cADR) such as toxic epidermal necrolysis (TEN), Stevens-Johnsonsyndrome (SJS), exfoliative dermatitis (ED) and drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), which are unwanted comorbidities in epilepsy. It was first discoveredthat the HLA-B*15:02 allele was strongly associatedwith carbamazepine(CBZ)-induced SJS/TEN amongHan Chinese and this ledto the discovery of other HLAallelesand cytochrome P450 (CYP) genes that were significantly associatedwith various AED-inducedcADRsacross variouspopulations. This mini-reviewis an update on the latest findings ofthe involvement of various HLA alleles and CYP alleles in cADRs caused by CBZ, phenytoin (PHT), oxcarbazepine (OXC) and lamotrigine(LTG) in different case-control studies around the world. From our review, we found that CBZ-and PHT-induced cADRsweremore commonly reportedthan the other AEDs.Therefore,there were morerobust pharmacogenetics studies related to these AEDs. OXC-and LTG-induced cADRswereless commonly reported,and somore studies are needed to validate the reported association of the newer reported HLA alleles with theseAEDs. It is also importantto considerthe allelic frequency within a given population before concludingthe use of thesealleles as genetic markers to prevent AED-induced cADR. Overall, the current body of research pointto a combination of alleles as a better pharmacogenetic marker comparedto the use of a single gene as a genetic marker for AED-induced cADR.

Matched MeSH terms: Phenytoin

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