Association between PK/PD-involved gene polymorphisms and carbamazepine-individualized therapy

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From: Pharmacogenomics(Vol. 16, Issue 13)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 9,559 words
Lexile Measure: 1740L

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Author(s): Chun-Lai Ma aff1 , Zheng Jiao aff1 , Xun-Yi Wu aff2 , Zhen Hong aff2 , Zhi-Yuan Wu aff3 , Ming-Kang Zhong [*] aff1

Keywords:

ABCC2 ; carbamazepine; carbamazepine 10,11-epoxide; EPHX1 ; epilepsy; genetic polymorphisms; SCN1A

Since carbamazepine (CBZ) was approved in 1974, it has widely been used as a first-line antiepileptic drug (AED) for partial epilepsy because of its good efficacy. However, because of its narrow therapeutic index (4-12 mg/l), large interindividual variability with respect to dose and adverse drug reactions, therapeutic drug monitoring (TDM) for CBZ is recommended [1 ]. What causes the large variability in the pharmacokinetic (PK) and pharmacodynamic (PD) properties of CBZ? In addition to its complex PK properties, evidence suggests a link between variations in genes involved in the PK properties of CBZ and the response to or the required dose of this AED [2 ].

CBZ acts by binding to the [alpha]-subunits of voltage-sensitive sodium channels, which are encoded by the SCN1A, 2A, 3A and 8A genes [3 ]. The SCN1A IVS5-91G[greater than]A (rs3812718) variant correlates with the maximum and maintenance doses of phenytoin (PHT) and CBZ [4-6 ], as well as with CBZ resistance [7 ]. However, these associations were not replicated in subsequent studies [ 8-10 ].

The metabolism of CBZ is complex. First, CBZ is extensively metabolized to CBZ 10,11-epoxide (CBZE) in the liver, primarily via the cytochrome P450 enzyme system, resulting in the excretion of less than 5% of an oral dose as unmodified CBZ in the urine [11 ]. CBZE, the first product of the primary pathway of CBZ metabolism, displays anticonvulsive properties and may be responsible for the side effects of CBZ treatment [12 ]. Certain toxic symptoms might occur at CBZE plasma concentrations greater than 3.2 μg/ml [13,14 ]. The isoenzyme CYP3A4, the predominant form of CYP in the adult liver, is responsible for the metabolism of most drugs (45-60%) and is involved in the formation of CBZE [11 ]. Another isoenzyme, CYP3A5, plays a minor role in CBZE metabolism. However, a recent in vitro study demonstrated that the metabolic capacity of CYP3A5 for CBZ is comparable to that of CYP3A4 [15 ]. Among the variants of CYP3A4/5 genes, CYP3A4*1G is the most common genetic variation among the Chinese population [ 16 ]. The CYP3A5*3 allele was reported to cause the loss of CYP3A5 activity and was suggested to influence the disposition of CBZ in epileptic patients [17 ]. However, the effects of these two genes on the dose and concentration of CBZ remain unclear.

CBZE is further converted to the inactive water-soluble metabolite CBZ 10,11-diol (CBZD) by microsomal epoxide hydrolase (mEH), which is encoded by the EPHX1 gene. The common variant EPHX1 c.337T[greater than]C alters the expression and activity of this enzyme both in vitro and in vivo [18-20 ]. Furthermore, this variant has been reported to be associated with the maintenance dosage and the normalized concentration of CBZ based on univariate SNP analyses [6 ]. Glucuronidation is another important CBZ detoxification pathway. The N-glucuronide of CBZ and the glucuronides of its hydroxylated...

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Gale Document Number: GALE|A428515777