Pharmacokinetic effects of capsaicin on vinblastine in rats mediated by CYP3A and Mrp2

Capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, P‐gp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC_0–t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food–drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.     

Pharmacokinetics and metabolism of Chf197, a ligustrazine derivative,in rats

Ligustrazine is the most abundant and bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular diseases. Chf197 is one of the structurally modified ligustrazine derivatives in a purpose of overcoming the rapid metabolism and short half‐life of original. The plasma and urine pharmacokinetics of Chf197 in rats were studied after intravenous or intraperitoneal injection of Chf197 with the validated RP‐HPLC method. The pharmacokinetic parameters of Chf197 injected intravenously 20 mg/kg were as follows: C_max, 1.44 ± 0.4 mg/L; T_max, 0.08 h; t_1/2, 3.03 ± 1.67 h; AUC, 3.85 ± 3.88 h/L; V_d, 31.66 ± 11.79L/kg; and CL, 9.29 ± 4.92 l/h/kg. Dose‐dependent pharmacokinetics was observed, and a significantly higher dose‐normalized AUC after intravenous administration was obtained than that after intraperitoneal administration. A possible metabolite was detected at about 3.1 min, and full‐scan mass spectrum was adopted to predict its possible structure.     

X射线照射对MRE11在鼻咽癌细胞株CNE1中表达的影响

目的 研究X射线照射后肿瘤细胞中MRE11基因及其蛋白表达的规律,并探讨其与肿瘤放疗失败的相关性,为提高肿瘤放射治疗疗效开辟新途径,提供新的靶点。方法 选取人鼻咽癌CNE1细胞株进行体外培养及X线照射。按单次照射0 Gy、2 Gy、4 Gy、6 Gy、8 Gy剂量分组,照射后4 h收集,利用RT-PCR技术检测MRE11 m RNA的表达;CNE1细胞株单次照射4 Gy于0 h、1.5 h、4 h、6 h、8 h、12 h、24 h时间点收集固定,利用免疫荧光技术检测MRE11蛋白的表达,并采用Image-Pro Plus 5.0软件分析测定各组荧光的平均光密度值(m OD)。结果 RT-PCR检测CNE1细胞株分别经0 Gy、2 Gy、4 Gy、6 Gy、8 Gy X线照射后4 h,各组之间MRE11 m RNA表达无统计学差异。免疫荧光技术检测CNE1细胞株经4 Gy X线照射后0 h、1.5 h、4 h、6 h、8 h、12 h、24 h时间点MRE11蛋白的表达,荧光强度先增强后减弱,4 h荧光强度最强。结论 CNE1细胞株MRE11 m RNA的表达与X线照射剂量递增无相关性。但CNE1细胞株经X线照射后MRE11蛋白的表达随时间的延长先增强后减弱,且在照射4 h表达最强,24 h后恢复到未照射水平。     

Effect of berberine on hepatocyte proliferation,inducible nitric oxide synthase expression,cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats

This study investigated the effect of berberine on the early phase of hepatocarcinogenesis stimulated by diethylnitrosamine (DEN, 150 mg/kg, 4 weeks) plus phenobarbital (PB, 75 mg/kg, 7 days) in rats. The expressions of proliferating cell nuclear antigen (PCNA) and inducible nitric oxide synthase (iNOS) were evaluated by immunohistochemistry. The activities of CYP isoenzymes were analyzed using different probe drugs including chlorzoxazone (CYP2E1) and phenacetin (CYP1A2) by high-performance liquid chromatography (HPLC) in vivo or in vitro. Results showed that the expressions of PCNA and iNOS were induced by DEN plus PB in liver tissues. Oral administration of berberine (50 mg/kg) inhibited the hepatocyte proliferation and iNOS expression, decreased cytochrome P450 content, inhibited activities of CYP2E1 and CYP1A2 in DEN-plus-PB-treated rats in vivo. Moreover, berberine (10, 50 and 100 μM) inhibited the activities of CYP2E1 and CYP1A2 in microsomes isolated from DEN-plus-PB-treated rats in vitro, suggesting that anti-hepatocarcinogenetic potential of berberine might be due to inhibiting oxidative metabolic activities of CYP 2E1 and CYP1A2, and decreasing NO production in rats.     

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron

Objective  The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. Materials and methods  In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. Results  The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%). Conclusion  None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated. Presented as an invited lecture at the Supportive Care in Cancer MASCC/ISOO 2008 International Symposium in Houston, TX, USA on June 26–28, 2008 This work was sponsored by GlaxoSmithKline. R Stoltz received funding from GlaxoSmithKline to conduct this study. All other authors were employees of GlaxoSmithKline.     

全脑放疗对大鼠血-脑脊液屏障功能的影响

目的通过检测顺铂在脑组织中的浓度变化,观察全脑常规分割外照射对血-脑脊液屏障通透性的影响。方法将Wistar大鼠50只随机分为0、10、20、30、40Gy组,每组10只,用6MV的X线加1.0cm厚组织补偿进行全脑常规分割外照射,每次2Gy,每天照射1次,每周照射5d。各组大鼠完成既定照射总量后16h经腹腔注射顺铂（1.0mg/kg）,20min后采集静脉血及脑组织,采用高效液相色谱法测定血清和脑组织中顺铂的浓度。结果各组大鼠血清中顺铂浓度比较差异无统计学意义（F=0.16,P〉0.05）。大鼠脑组织中顺铂的浓度随照射剂量的增加而逐渐增高,各组间比较差异有显著性（F=63.12,q=2.231～18.005,P〈0.05、0.01）。结论放射治疗可增加血-脑脊液屏障通透性,全脑放疗20～30Gy时为加用化疗的最佳时机。     

Sumatriptan reduces severity of status epilepticus induced by lithium–pilocarpine through nitrergic transmission and 5‐HT1B/D receptors in rats: A pharmacological‐based evidence

Status epilepticus (SE) is a life‐threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti‐inflammatory property of the anti‐migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole‐induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium–pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5‐hydroxytryptamin 1B/1D (5‐HT_1B/1D) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127 mg/kg, i.p) and pilocarpine (60 mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001‐1 mg/kg, i.p.) improved it (P < 0.001). Administration of the selective 5‐HT_1B/1D antagonist GR‐127935 (0.01 mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01 mg/kg, i.p.). Although both tumor necrosis factor‐α (TNF‐α) and NO levels were markedly elevated in the rats' brain tissues post‐SE induction, pre‐treatment with sumatriptan significantly reduced both TNF‐α (P < 0.05) and NO (P < 0.001) levels. Combined GR‐127935 and sumatriptan treatment inhibited these anti‐inflammatory effects of sumatriptan, whereas combined non‐specific NOS (L‐NAME) or selective neuronal NOS (7‐nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5‐HT_1B/1D receptors, neuroinflammation, and nitrergic transmission.     

Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants

We evaluated the effect of the pregnane X receptor (PXR) agonist rifampin on metformin pharmacokinetics, organic cation transporter 1 (OCT1) and OCT2 mRNA levels, and glucose levels, using the oral glucose tolerance test (OGTT) in 16 healthy subjects. The glucose-lowering effects of metformin were evaluated by OGTT before and after metformin treatment on days 1 and 2 and again on days 13 and 14 after a 10-day course of rifampin. Rifampin increased the difference in maximum glucose levels (ΔG(max)) by 41.9% (P = 0.024) and the area under the concentration-time curve (AUC) during the first 60?min after glucose ingestion (ΔAUC(gluc60)) by 54.5% (P = 0.020). Renal clearance (CL(R)) of metformin was increased by 16% (P = 0.008), but the systemic exposure was only slightly increased (13%, P = 0.049), possibly because of increased absorption. Rifampin increased OCT1 mRNA levels 4.1-fold in peripheral blood cells (P = 0.001); however, OCT2 mRNA was not detected. Our results suggest that rifampin increases OCT1 expression and hepatic uptake of metformin, leading to enhanced glucose-lowering action.     

Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients

OBJECTIVE: Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living-donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus. METHODS: Data were collected retrospectively from 130 de novo pediatric liver transplant recipients treated with tacrolimus during the first 50 postoperative days. Pharmacogenomic data including both the CYP3A5*3 polymorphism and messenger ribonucleic acid (mRNA) expression levels of MDR1, CYP3A4, and CYP3A5 in the native intestine and the graft liver at transplantation were obtained from 65 of the recipients. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modeling program NONMEM to estimate population mean parameters of apparent clearance (CL/F) and apparent volume of distribution (V/F). RESULTS: Both CL/F and V/F were allometrically related to body weight, and CL/F decreased when the AST value was elevated. CL/F increased linearly in the immediate postoperative period but did not change with time after postoperative day 21. The intestinal MDR1 mRNA level significantly influenced the initial CL/F (P < .005). Furthermore, the increase in CL/F over time was 2 times higher (95% confidence interval, 1.19-2.81 times; P < .005) in recipients of a CYP3A5*1-carrying graft liver than in patients with the hepatic CYP3A5*3/*3 genotype. The Bayesian prediction for tacrolimus concentrations was not significantly biased on any postoperative day, and the mean absolute prediction error was lower than 3 ng/mL after the first 2 weeks of transplantation. CONCLUSIONS: The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation.     

在放射性肾损伤纤维性修复中的分子病理机制

目的为探讨纤溶酶原激活物抑制因子-1(PAI-1)在放射性肾损伤纤维性修复中的作用和意义,揭示其发病的分子病理机制。方法24只雄性健康的Wistar大鼠以30Gy60Coγ线单次双肾局部照射,于照射后4个不同时相点活杀,取肾组织进行常规病理学观察及原位分子杂交,观察PAI-1mRNA表达的变化。结果纤维化的肾组织PAI-1表达较正常对照组增高,与纤维化程度呈正相关。结论PAI-1可能在肾放射性损伤后纤维性修复的发生及发展中起重要的作用。     

A template model for studying anticancer drug efflux transporter inhibitors in vitro

Efflux transporters play an important role in drug absorption and also in multidrug resistance. ABCG2 (BCRP) is an efflux transporter conferring cross‐resistance to mitoxantrone (Mit), irinotecan (CPT11), and its active metabolite SN38. MBLI87, a new ABCG2 inhibitor has proven its efficacy against ABCG2‐mediated efflux in vitro and in vivo. This work aimed at modeling and quantifying the cellular interaction between MBLI87 and different substrates using a mechanistic template model. An in vitro competition experiment study was carried out with HEK293 cells overexpressing ABCG2 exposed to fixed concentrations of substrates (Mit, CPT11, SN38) and to MBLI87 at several concentration levels. A nonlinear mixed‐effects transport inhibition model was developed to fit intracellular drug concentrations. In this model, drugs cross the cell membrane through passive diffusion, active drug efflux is ABCG2 mediated, interaction between substrates and inhibitor occurs within the transporter. The interaction was found to be noncompetitive. The MBLI87 Ki was estimated to 141 nm for Mit, 289 nm for CPT11, and 1160 nm for SN38. The ratio of intrinsic transport clearance divided by diffusion clearance was estimated to 2.5 for Mit, 1.01 for CPT11, and 5.4 for SN38. The maximal increase in the intracellular substrate concentration that is possible to achieve by inhibition of the transporter was estimated to 1.5 for Mit, 0.1 for CPT11, and 4.4 for SN38. This mechanistic template model describes both drug accumulation and cellular transport, and the mixed‐effects approach allows an estimation of intra‐ and interassay variability. This model is of great interest to study cytotoxic cellular pharmacokinetics.     

Role of CYP3A in haloperidol N-dealkylation and pharmacokinetics in rats

Haloperidol (HP), an antipsychotic drug, is N-dealkylated by cytochrome P450 (CYP) to 4-fluorobenzoylpropionic acid (FBPA). The purpose of this study was to identify whether CYP3A metabolizes HP to FBPA in hepatic microsomes of rats and to investigate whether an inhibitor or an inducer of CYP3A affects HP pharmacokinetics in rats. The rate of FBPA formation was determined in hepatic microsomes from 8-week-old male Sprague-Dawley rats. Among several specific CYP isozyme inhibitors including troleandomycin (TAO), diethyldithiocarbamate, furafylline and quinine, only TAO showed marked inhibition of FBPA formation. Anti-rat CYP3A serum inhibited FBPA formation by 76.4%, while other anti-rat CYP sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly did. In a pharmacokinetic study, 8-week-old male Sprague-Dawley rats were given 0.5 mg/kg HP intravenously after treatment with 100 mg/kg erythromycin, a CYP3A inhibitor, or 80 mg/kg dexamethasone, a CYP3A inducer, intraperitoneally once a day for 7 days or 2 days, respectively or untreated. HP half-life was prolongated to 171% of the average control value by erythromycin and shortened to 49% of control by dexamethasone. HP clearance was reduced to 63% of control by erythromycin and was increased to 167% of control by dexamethasone. These results suggested that CYP3A mainly catalyzed HP to FBPA in rats, and the modification of this enzyme activity would affect the pharmacokinetics of HP.     

Pharmacokinetics of an everninomicin (SCH 27899) in mice, rats, rabbits, and cynomolgus monkeys following intravenous administration

The pharmacokinetics of SCH 27899, a novel oligosaccharide compound of the everninomicin class with excellent activity against gram-positive strains, was studied with mice, rats, rabbits, and cynomolgus monkeys following intravenous administration as SCH 27899-N-methylglucamine-hydroxypropyl beta-cyclodextrin. Concentrations of SCH 27899 in mouse serum, rat plasma, and rabbit serum were determined by a high-pressure liquid chromatography method on a poly(styrene-divinyl benzene) column, and those in monkey plasma were determined by a paired-ion chromatographic method. Plasma and serum concentrations of SCH 27899 exhibited a biexponential decline in all species following intravenous administration. The half-lives at beta phase were 3.0 to 7.9 h in mice, rats, and rabbits and 24 h in cynomolgus monkeys. There was a linear relationship between the area under the curve extrapolated to infinity [AUC(I)] in mice and dose. Rabbits also exhibited dose proportionality in AUC(I). However, in rats, increasing the dose from 3 to 60 mg/kg of body weight resulted in a 49-fold increase in AUC(I). When the species was changed from mouse to rat, rabbit, or cynomolgus monkey, AUC(I) increased, whereas clearance (CL) decreased. It was concluded that the pharmacokinetics of SCH 27899 in animals varied with species; CL was the highest in mice and rats, followed by rabbits and cynomolgus monkeys.     

Effects of clarithromycin on the pharmacokinetics of tacrolimus and expression of CYP3A4 and P-glycoprotein in rats

The objective of this study was to investigate the effect of clarithromycin on the pharmacokinetics of tacrolimus in rats and better understand its mechanism. In the control group (n = 6), rats received a single oral dose of 1 mg tacrolimus on day 6. In the experimental group (n = 6), rats received 0.25 g of clarithromycin daily for five consecutive days and then a single oral dose of 1 mg tacrolimus on day 6. Orbital venous blood (250 μL) was collected at 0, 0.25, 0.50, 0.75, 1, 2, 4, 8, 12, and 24 h before and after tacrolimus administration. Blood drug concentrations were detected via mass spectrometry. Small intestine and liver tissue samples were collected after rats were euthanized via dislocation, and CYP3A4 and P-glycoprotein (P-gp) protein expression was determined using western blotting. Clarithromycin increased the blood tacrolimus concentration and affected its pharmacokinetic properties in rats. Compared with those in the control group, the AUC_0–24, AUC_0–∞, AUMC_(0–t), and AUMC_(0–∞) of tacrolimus in the experimental group were significantly increased, whereas the CLz/F was significantly lower (P < 0.01). Simultaneously, clarithromycin significantly inhibited CYP3A4 and P-gp expression in the liver and intestine. Protein expression of CYP3A4 and P-gp in the liver and the intestinal tract was significantly downregulated in the intervention group compared with that in the control group. Clarithromycin significantly inhibited the protein expression of CYP3A4 and P-gp in the liver and intestine, thereby increasing the mean blood concentration and significantly increasing the AUC of tacrolimus.     

Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants,a population pharmacokinetic modelling approach

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7–10 kg; patient's postnatal age: 0–206 days; GA: 27–42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1–10.6 mg/kg) per day was administered by 30‐min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed‐effect population model software). Data were modelled with an allometric pharmacokinetic model, using three‐fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (V_d) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, V_d, F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.     

Enhancement of bone regeneration with the accordion technique via HIF‐1α/VEGF activation in a rat distraction osteogenesis model

Axial micromotion of bone fragments promotes callus formation and bone healing during the process of distraction osteogenesis (DO). This study investigated the effects of the combined axial compression and distraction (accordion) technique on bone regeneration in rat DO model. Male Sprague–Dawley rats (n = 62) underwent right tibial transverse osteotomy and were randomly divided into four groups after lengthening: control (no manipulation) and three experimental groups assigned on the basis of the period of accordion manoeuvres in the consolidation phase (Groups 1, 2, and 3 with accordion technique applied at Weeks 1, 3, and 5, respectively). Animals were terminated at 1 week after each accordion phase (i.e., Weeks 2, 4, and 6). Callus formation was monitored by X‐ray radiography; new bone quality was evaluated by microcomputed tomography, histological analysis, and mechanical testing. Serum levels of hypoxia‐inducible factor (HIF)‐1α and vascular endothelial growth factor (VEGF) were measured. Callus formation after accordion manoeuvre at Week 3 (Group 2) increased significantly over time of consolidation. The microcomputed tomography and mechanical analysis revealed Group 2 had more newly formed bone and superior mechanical properties in contrast to the other groups at termination. Histomorphological and immunohistochemical analyses confirmed a greater degree of osteogenesis and angiogenesis corresponding to increased serum levels of HIF‐1α and VEGF in Group 2. The accordion technique was effective in promoting bone consolidation via activation of HIF‐1α/VEGF during DO. The accordion technique may be used in the middle phase of bone consolidation to promote bone formation in patients undergoing DO treatment.     

Population Pharmacokinetics and AUC-Guided Dosing of Tobramycin in the Treatment of Infections Caused by Glucose-Nonfermenting Gram-Negative Bacteria

PurposeTobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia.MethodsThis retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and V_d in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre^0.568, interindividual variability [IIV] = 31.1%; V_d = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%).FindingsThe final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968–1.003) and serum albumin (OR = 0.137; 95% CI, 0.022–0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040–1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000–1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m² be followed by therapeutic drug monitoring at peak and 24 hours after the first dose.ImplicationsThis study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing.     

Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

What is known and Objective: Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P‐glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T‐G2677T/A‐C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects. Methods: Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC‐MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed‐effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs. Results and Discussion: Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A4*18B and CYP3A5*3 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter‐subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/*1‐CYP3A5*3/*3 was 10·3 L/h and was 48·5% in those not carrying CYP3A4*1/*1‐CYP3A5*3/*3. What is new and Conclusion: This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1‐CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.     

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia

OBJECTIVES: Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. METHODS: Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. RESULTS: CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). CONCLUSION: We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.