Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects

Abstract

BackgroundBupropion (BUP) is an antidepressant and its pharmacological activity is mediated by its major metabolite, hydroxybupropion (HBUP). We investigated the effects of genetic polymorphisms of CYP2B6 on BUP and HBUP to provide certain evidence on the clinical rational administration of BUP.Material/MethodsPlasma BUP and HBUP concentrations were assayed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).ResultsA total of 23 healthy volunteers (eleven participants with CYP2B6*1/*1, 7 participants with CYP2B6*1/*6, 3 participants with CYP2B6*4/*6, and 2 participants with CYP2B6*1/*4) received orally administered 150 mg of BUP according to protocol. Blood samples were obtained up to 96 hours after administration. The whole blood was subject to genotyping by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The concentration-time curve (AUC(0®96)), maximum plasma concentration (Cmax), and terminal half-life (t1/2) values of BUP in CYP2B6*1/*4 were lower than those of CYP2B6*1/*1. By contrast, the time to Cmax (tmax) value of the former was higher than that of the latter. The HBUP AUC(0®96) values in CYP2B6*4/*6 and CYP2B6*1/*4 increased to values 1.12-fold and 1.98-fold, compared with CYP2B6*1/*1 carriers. However, the HBUP AUC(0®96) value in CYP2B6*1/*1 was 1.51-fold higher than that in CYP2B6*1/*6. Similarly, the HBUP Cmax values in CYP2B6*4/*6 and CYP2B6*1/*4 increased by 1.12-fold and 1.97-fold, whereas the HBUP Cmax value in CYP2B6*1/*6 decreased to a value 1.64-fold lower than that in CYP2B6*1/*1.ConclusionsGenetic polymorphisms of CYP2B6 influence the pharmacokinetic parameters of BUP and HBUP and thus establish rational BUP administration for Chinese patients in clinical settings.

Stereoselective Bupropion Hydroxylation by Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase Genetic Variants

“…In vitro-in vivo concordance is less consistent for CYP2B6*4 than for decreased metabolism polymorphisms, which may be influenced by the rarity of CYP2B6*4. CYP2B6.4 had minimally increased bupropion hydroxylation in vitro, and numerically but not significantly higher plasma hydroxybupropion/bupropion AUC ratios in CYP2B6*4 hererozygotes for the racemate (Kirchheiner et al, 2003;Zhu et al, 2012;Ma et al, 2018;Kharasch and Crafford, 2019) and enantiomers (Kharasch and Crafford, 2019). Based on these patterns, and the present in vitro results, it could be expected that other CYP2B6 polymorphisms coding for diminished (*5, *6, *7, *9, *19, *26) or defective (*16) in vitro bupropion hydroxylation might result in diminished in vivo bupropion hydroxylation.…”

“…The influence of CYP2B6*6, which consistently results in diminished bupropion hydroxylation in vitro (Table 3), is highly concordant in vivo. Plasma racemic hydroxybupropion/bupropion AUC ratios after single-dose bupropion were lower in CYP2B6*6 carriers than noncarriers (Chung et al, 2011), lower in CYP2B6*6/*6 and CYP2B6*1/*6 versus CYP2B6*1/*1 genotypes (Gao et al, 2016;Lv et al, 2016), and hydroxybupropion concentrations were lower in CYP2B6*6 heterozygotes than wild-types (Ma et al, 2018). Assessed stereoselectively, plasma AUC ratios and urine hydroxybupropion formation clearances for both bupropion enantiomers, after a single bupropion dose, were lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes (Kharasch and Crafford, 2019).…”

Effects of high-fat diet and CYP2B6 mutants on the pharmacokinetics of bupropion and hydroxybupropion among healthy chinese subjects

“…Forty-four healthy Chinese volunteers were recruited for this study. Subjects were all male, weighted 60-80 kg, aged 18-28 years, and had a normal body mass index range (19-24 kg/m 2 ) [14]. Drugs, alcohol and caffeine-containing beverages, cigarettes, and nutritional supplements were refrained a week before commencement and throughout the study [15].…”

“…Drugs, alcohol and caffeine-containing beverages, cigarettes, and nutritional supplements were refrained a week before commencement and throughout the study [15]. [14] The clinical protocols of fasting and feeding study were designed in a randomized two-process, two-phase, twosequence, and crossover manner with a 2-week washout period [16,17]. In fasting study without breakfasting on day 1, subjects orally received 150 mg BUP (a tablet of 150 mg BUP SR; Disha, Shandong, China) or 150 mg BUP (a tablet of 150 mg BUP SR; Jingxin, Zhejiang, China) with 200 mL of water at 8:00 am.…”

“…Feeding study was designed as the same as fasting study except the high-fat breakfasting, containing one fried egg, one portion of hash brown potatoes, 220 mL of pure milk, and one drumstick 30 min prior to administration. Serial blood samples (5 ml) were collected using a forearm indwelling venous catheter 1 h prior to dosing and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72 and 96 hour after BUP oral administration [14]. These blood samples were stored in EDTA-K 2 tubes, and then centrifuged at 3000 rpm for 30 min.…”