Bi-Kui Zhang

Impact of MDR1 Haplotypes Derived from C1236T, G2677T/A and C3435T on the Pharmacokinetics of Single-Dose Oral Digoxin in Healthy Chinese Volunteers

Objective: To investigate the effect of single-nucleotide polymorphisms (SNPs) and the haplotypes of MDR1 on the pharmacokinetics of single-dose digoxin in healthy Chinese volunteers. Methods: After the genotypes of the MDR1 alleles of interest (G1199A, C1236T, G2677T/A and C3435T) had been determined, 20 subjects with the predominant haplotypes (TTT, CGC, TGC and CAC, in the order of position 1236-2677-3435) were selected and administered with 0.25 mg of digoxin. Venous blood samples were taken from 0 to 4 h after dosing, and the pharmacokinetic parameters were calculated using the Drug and Statistics software. Results: No mutation allele of G1199A was found in this study, the frequencies of the C1236T, G2677T/A and C3435T genetic variants were 65.2, 41.2, 17.3 and 39.7%, respectively. The 4 haplotypes TTT, TGC, CGC and CAC were present in more than 90% of Chinese Han subjects, and an incomplete linkage between C3435T in exon 26, G2677T in exon 21 and C1236T in exon 12 was found. The peak concentration in plasma, the time to reach the peak concentration and the area under the plasma concentration/time curve between 0 and 4 h were used as indices of digoxin absorption. They were significantly different between subjects with the haplotypes TGC-CGC and those with TTT-TTT (p < 0.05). No significant difference was found when volunteers were grouped according to the haplotypes derived from G2677T and C3435T or disparate SNPs. Conclusion: Our findings indicated that the MDR1 haplotype derived from C1236T, G2677T/A and C3435T is superior to predict the pharmacokinetics of digoxin. Digoxin pharmacokinetics are significantly different between individuals with the TTT-TTT haplotype and those with TGC-CGC.

Effects of Ginkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects.

AimIt has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that GBE may alter the metabolism of diazepam.MethodsThe pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10xa0mg) in the absence or presence of oral GBE (120xa0mg bid, for 28xa0days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method.ResultsThe 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80–125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC0–408 with GBE to AUC0–408 without GBE was 95.2 (90%CI: 91.6–98.8) and 101.8 (90%CI: 99.4–104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported.ConclusionThe above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.

Effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia

ObjectiveTo study the effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia.MethodsNineteen patients received multiple doses of quetiapine (200xa0mg, twice daily) with or without co-administered erythromycin (500xa0mg, three times daily). Blood samples were collected at specified time intervals for determination of plasma concentrations of quetiapine and some of its metabolites.ResultsWith erythromycin co-administration: for quetiapine, maximal plasma concentration (Cmax), area under concentration–time curve of 0–∞xa0h (AUC0–∞) and terminal-phase elimination half-life time (t1/2) increased 68, 129 and 92%, respectively, and clearance (CL) and terminal elimination rate constant (Ke) decreased 52% and 55%, respectively; for quetiapine sulfoxide (QTP-SF), Cmax, AUC0–∞ and AUC ratio decreased 64, 23, and 70%, respectively, and t1/2 increased 211%; for 7-hydroxy-quetiapine (QTP-H), Ke and AUC ratio decreased 61% and 45%, respectively, and t1/2 increased 203%; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), Cmax, AUC0–∞ and AUC ratio decreased 36, 40 and 71%, respectively.ConclusionErythromycin has a noticeable effect on the metabolism of quetiapine. When quetiapine is co-administered with CYP3A inhibitors such as erythromycin, the dosing regimen should be modified according to quetiapine TDM.

The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation

Triptolide (TP), an active ingredient of Tripterygium wilfordii Hook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50u2009nM) for 24u2009h after pretreatment with ISL and GA (5, 10, and 20u2009μM) for 12u2009h and 24u2009h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.

Development and validation of an LC-MS/MS method for the determination of tolvaptan in human plasma and its application to a pharmacokinetic study.

Tolvaptan is a selective vasopressin V(2)-receptor antagonist mainly used for the treatment of hyponatremia. This study described the development and validation of an LC-MS/MS method for the determination of tolvaptan in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 2-demethyl tolvaptan (internal standard, IS). Chromatographic separation was performed on a Zorbax XDB C(18) column with an isocratic mobile phase consisting of water (containing 0.1% formic acid) and methanol (25:75, v/v). Determination of the analytes was achieved by tandem-mass spectrometry with positive electrospray ionization. The multiple reaction monitoring (MRM) transitions were performed at m/z 449.2→252.1 for tolvaptan and m/z 435.2→238.1 for IS. The assay was linear over the concentration range of 0.457-1000ng/mL, with a lower limit of quantification of 0.457ng/mL. The intra- and inter-day precisions at three concentration levels (0.914, 111 and 800ng/mL) were less than 15% and their accuracies were within the range of 97.7-107.8%. The mean recovery ranged from 99.2 to 104.6% and the matrix effect from 89.3 to 99.5%. Tolvaptan was stable under all tested conditions. This validated method was successfully applied to a pharmacokinetic study in healthy volunteers after oral administration of single-dose tolvaptan tablets.

Effect of amlodipine on the pharmacokinetics of tacrolimus in rats.

Abstract 1. The immunosuppressant tacrolimus (TAC) is a substrate of cytochrome P450 3A2 (CYP3A2) and P-glycoprotein (P-gp) in rats. Amlodipine (AML) is an inhibitor of CYP3A2 in rats. We investigated the effect of AML on the pharmacokinetics of TAC in rats. 2. When co-administered with TAC orally or intravenously, AML decreased the oral clearance and raised the blood concentration of TAC in rats, but the T1/2 of TAC was not significantly affected by AML. Upon oral administration of TAC, the effect of 15u2009mg/kg of AML on the AUC of TAC was lower than that seen with 5 or 10u2009mg/kg. However, upon intravenous TAC administration, the effect of 15u2009mg/kg of AML on the AUC of TAC was higher than that seen with 5u2009mg/kg. 3. AML is an inhibitor of P-gp and CYP3A2 in rats. If AML and TAC are co-administered orally, AML elicits greater inhibition in P-gp than CYP3A2 during first-pass metabolism. If AML is given orally and TAC given intravenously concurrently, AML mainly inhibits CYP3A2 activity and increases the blood concentration of TAC. There are significant pharmacokinetic interactions between TAC and AML. AML raises the blood concentration of TAC in rats probably by inhibiting P-gp and CYP3A2.

Pharmacokinetics and tolerability of modafinil tablets in Chinese subjects.

Objective:u2002 To investigate the pharmacokinetics and tolerability of modafinil in Chinese subjects.

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters

Triptolide (TP), the main bioactive component of Tripterygium wilfordii Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, and OATP2 were also induced. In addition, in vitro transport assays identified that neither was TP exported by MRP2, OATP1B1, or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity.

An LC–MS/MS method for determination of bioactive components of licorice and Semen Strychni in rat plasma: application to a pharmacokinetics study

Semen Strychni is known for its treatment of rheumatic arthritis with a low therapeutic index. Liquorice contributes a lot in herb detoxification according to the traditional Chinese medicine theory. A simple, rapid, and sensitive liquid chromatography-mass spectrometric method (LC-MS) was developed and validated for simultaneous determination of main bioactive ingredients in liquorice and Semen Strychni in rat plasma. Using moclobemide and cyproterone acetate as the internal standards, the analytes were pretreated via protein precipitation with methanol. An Ultimate AQ-C18 column (3.0xa0μm, 3.0xa0×xa0100xa0mm) was employed for chromatographic separation, combining with gradient elution. The mobile phase consisted of 0.07% formic acid and 0.12% ammonium acetate in aqueous phase (A) and acetonitrile in organic phase (B). The elution program was as follows: 0-0.5xa0min, 20% B; 0.5-1xa0min, 20-60% B; 1-7xa0min, 60-85% B; and 7-7.5xa0min, returned to 20% B, then continued to 12xa0min. Selected reaction monitoring was performed in both positive and negative ESI. Positive mode was adopted for detection of strychnine, brucine, and moclobemide, while negative mode was used for glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, liquiritin, and cyproterone acetate. The method was validated for specificity, linearity, matrix effect, recovery, precision, accuracy, and stability. The results show that this method is sensitive, accurate and robust for biological matrix analysis. Moreover, the proposed method was applied to a pharmacokinetic study in Sprague-Dawley rats for investigating the mechanism of which liquorice detoxifies Semen Strychni.

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients

The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections.