Effect ofCYP3A5*3genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients

Abstract

The serum concentrations of CBZ in 35 Korean epileptic patients were measured and their CYP3A5 genotype was determined. Fourteen patients were CYP3A5 expressors (two for CYP3A5*1/*1 and 12 for CYP3A5*1/*3) and 21 patients were CYP3A5 non-expressors (CYP3A5*3/*3). Dose-normalized concentrations (mean +/- SD) of CBZ were 9.9 +/- 3.4 ng/mL/mg for CYP3A5 expressors and 13.1 +/- 4.5 ng/mL/mg for CYP3A5 non-expressors (P = 0.032). The oral clearance of CBZ was significantly higher in CYP3A5 non-expressors than that of CYP3A5 expressors (0.056 +/-0.017 L/h/kg vs. 0.040 +/- 0.014 L/h/kg, P = 0.004). The CYP3A5 genotype affected the CBZ concentrations in Korean epileptic patients and is a factor that may contribute to inter-individual variability in CBZ disposition in epileptic patients.

Effect of CYP3A5 Genotypes on the Pharmacokinetics of Carbamazepine when used as Monotherapy or Co-Administered with Phenytoin, Phenobarbital or Valproic Acid in Thai Patients

“…A previous study by Seo et al of 144 Japanese epileptic patients reported that patients with CYP3A5*3/*3 exhibited CBZ clearance 8% higher than patients not carrying CYP3A5*3/*3 [15]. This result conflicted with the result from the study by Park et al of 35 Korean epileptic patients, who reported that the CBZ clearance in patients with homozygous CYP3A5*3/*3 was 29% lower than that observed in patients with at least one CYP3A5*1 allele [16]. Seo et al [15] recruited patients who used CBZ as either monotherapy or concurrently with the potent inducer of CYP3A, i.e.…”

“…CBZ level and CBZ CL/F showed no significant difference between groups of different genotypes (comparisons of the categorized patients into three groups are not shown). These results conflict with the results reported by Park et al, who reported that the mean of dose-adjusted CBZ level in CYP3A5 expressors (9.94±3.38 mcg/L/mg) was significantly lower (p=0.032) than the mean of dose-adjusted CBZ level in CYP3A5 non-expressors (13.07±4.46 mcg/L/mg), while the mean of CBZ CL/F in CYP3A5 expressors (0.056±0.017 L/kg/hr) was significantly higher (p=0.004) than the mean of CBZ CL/F in CYP3A5 non-expressors (0.040±0.014 L/kg/hr) [16]. In our study, the mean of dose-adjusted CBZ level in CYP3A5 expressors was 11.06±3.92 mcg/L/mg, while the mean of CBZ level-to-dose ratio in CYP3A5 nonexpressors was 10.61±3.65 mcg/L/mg, meaning they were nearly equal and were not statistically significantly different (p=0.727).…”

“…Consequently, CBZ clearance was reported to be 29% significantly lower in patients with CYP3A5*3/*3 compared to the rate in patients with CYP3A5*1/*1 or CYP3A5*1/*3 (p = 0.004) [16]. The effects of CYP3A5* 3 on CBZ pharmacokinetics (PK) when co-medicated with other AEDs reported to have a pharmacokinetic interaction with CBZ have never been clearly defined.…”

“…We excluded pregnant women, patients with hepatic disease or renal disease. Additionally, patients who were concurrently using drugs which may interact with CBZ pharmacokinetics (except PHT, PB and VPA) were excluded, namely verapamil, diltiazem, haloperidol, theophylline, ticlopidine, cimetidine, omeprazole, trazodone, fluoxetine, risperidone, clarithromycin, erythromycin, rifampicin, isoniazid, isotretrinion, gemfibrozil and metronidazole [14][15][16]. Grapefruit consumers, if any, were excluded.…”

CYP3A5*3Polymorphism and Its Clinical Implications and Pharmacokinetic Role

“…Similar to other studies evaluating the role of CYP3A5*3 polymorphism, when we assessed the effect of CYP3A5*3 polymorphism on the pharmacokinetics of various CYP3A substrates, we found increased drug exposure or plasma drug levels for the following: simvastatin, alprazolam, risperidone, and carbamazepine. [47][48][49][50] In the case of alprazolam, [50] after a 1 mg dose was administered to healthy individuals, the area under the plasma concentrationtime curve (AUC) for alprazolam was significantly greater in subjects with the CYP3A5*3/*3 polymorphism (830.5 ng*h/mL) than in those with CYP3A5*1/*1 (599.9 ng*h/mL) (P=0.030), while the oral clearance was also significantly different between the CYP3A5*1/*1 (3.5 L/h) and CYP3A5*3/*3 groups (2.5 L/ h) (P=0.036). Simvastatin also showed similar results: after 20 mg simvastatin medication in healthy subjects, the AUC in the CYP3A5*1/*1 carriers (4.94 ng*h/mL) was significantly lower than in the CYP3A5*3/*3 carriers (16.35 ng*h/mL; P=0.013).…”