Reversible metabolism of vitamin K-vitamin K epoxide: modeling considerations and limitations.

Due to the cyclical natural of the vitamin K-vitamin K epoxide system, a two-compartment reversible metabolism model was used to describe this interconversion. In attempting to apply this model to the vitamin K-vitamin K epoxide cycle using literature data from dogs, interconversion and elimination clearances were obtained which are not physiologic. Consequently, the assumptions of the model were reexamined with respect to their validity. One critical assumption of the two-compartment model for interconversion is that it can only be applied in the absence of flow limitations. To determine what effect flow limitations may exert on the vitamin K and vitamin K epoxide apparent blood clearances, a model separating the liver from the blood compartment was proposed assuming the interconversion and metabolism of vitamin K and its epoxide occurred only within the liver. Simulated data suggested that if the reversible metabolic clearance values exceeded the distribution clearance terms, all the apparent clearances calculated using blood concentration-time data were in error. It is suggested that a two-compartment interconversion model might be too simplistic for the vitamin K-vitamin K epoxide cycle where the reversible metabolism is efficient and the distributional clearance may be rate limiting.     

Warfarin and vitamin K intake in the era of pharmacogenetics

The considerable variability in the warfarin dose–response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following:

1. The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy.
2. The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and
3. The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

     

Effect of diseases on response to vitamin K antagonists

Introduction The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs.

Methods We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione.

Discussion Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs.

Conclusion In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants.     

Risk Factors for Bleeding in Hospitalized Patients with Elevated INR: No Vitamin K Therapy Received Versus Vitamin K Received

Background:

Supratherapeutic international normalized ratio (INR) in patients on warfarin is a common side effect. Updated guidelines recommend against using vitamin K to correct INRs 4.5 to 10 in the absence of bleeding. The impact of compliance with updated guidelines during hospitalization has not been fully explored.

Methods:

A retrospective, observational study was performed utilizing electronic medical records. The goal was to evaluate management of supratherapeutic INR values for medicine inpatients and identify differences in clinical outcomes among inpatients treated and not treated with vitamin K. Records from adult inpatients with at least one INR value between 4.5 and 9 were reviewed. A total of 51 records were evaluated. Thirty-four patients did not receive vitamin K compared to 17 who did. Bleeding events, readmissions rates, length of stay, and familiarity with new guidelines were studied.

Results:

Mean age of patients was 73 years, and 71% were female. No statistically significant differences were observed in bleeding events between patients who received vitamin K and those who did not: 2/17 (12%) and 1/34 (3%), respectively (P = .30). No differences in 30-day readmission rates (24% vs 18%; P = .71) or in length of stay (7 vs 4 days; P = .11) were found. All pharmacists (13 of 13) were familiar with CHEST 2012 guidelines on the management of supratherapeutic INR compared to 10 of 21 (48%) hospitalists (P = .001).

Conclusions:

With the national focus on reduction of health care costs, health systems are looking at innovative ways to reduce readmission rates and length of stay. This study, which evaluated the use of vitamin K administration, showed no statistical difference between bleeding events, readmission rates, and length of stay in patients who received vitamin K. Education on the updates of guidelines may be beneficial, as many providers were not familiar with the changes in recommendations.     

Non-vitamin K oral anticoagulants versus vitamin K antagonists in the treatment of venous thromboembolic disease

Introduction: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the western world. The approval of non-vitamin K oral anticoagulants (NOACs) as antithrombotic alternatives to vitamin K antagonists (VKAs) has offered more treatment options to physicians for the prevention of VTE recurrence, fatal pulmonary embolism (PE) and long-term complications. Four NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) that have been approved for the treatment of acute VTE following large phase III trials, where NOACs demonstrated similar efficacy and superior safety profile compared to VKAs.

Areas covered: The purpose of this review article is to summarise current knowledge of oral anticoagulation for the treatment of acute VTE and to compare NOACs with VKAs, highlighting the factors that might influence the decisions of physicians. Data for this article were obtained through a search of PubMed for trials comparing NOACs with VKAs in acute VTE setting and articles or analyses that interpreted results from these trials.

Expert opinion: The NOACs have changed clinical practice regarding oral anticoagulation for acute VTE. Despite their advantages, ‘grey zones’ still remain and more studies are needed to provide evidence and confirm the superiority (or at least non-inferiority) of NOACs over VKAs. Real world data might give additional insights.     

华法林相关维生素K环氧化物还原酶复合体亚单位1及细胞色素P450 2C9基因型快速检测的方法研究

目的 建立一种快速、准确、简便、经济的检测维生素K环氧化物还原酶复合体亚单位1(VKORC1)和细胞色素P450 2C9(CYP2C9)基因型的方法.方法 提取220例肺栓塞患者外周血的DNA,针对2个基因的SNP位点设计特异性引物,并进行荧光聚合酶链反应(PCR),根据荧光PCR的熔解曲线分析样本的基因型.同时对样本进行传统的限制性酶切片段长度多态性(PCR-RFLP)基因分型,从时间、通量、费用、准确性等方面对2种方法进行比较.结果 VKORC1 1693G＞A和CYP2C9 1075A＞C两个SNP位点的不同基因型具有不同的熔解曲线峰型.220例样本中,VKORC1基因AA型184例,AG型34例,GG型2例,各占83.6％、15.5％、0.9％;CYP2C9基因*1/*1型201例,*1/*3型19例,各占91.4,％、8.6％,无*3/*3型纯合子.PCR-RFLP检测结果与上述结果基本相同.2种方法相比,前者较后者操作步骤少,用时少,费用相当,结果更准确.结论 利用荧光PCR检测VKORC1及CYP2C9的SNP分型操作简便、快速、经济、准确,适用于临床实验室开展基因分型.     

Evaluation of Education on the Appropriate Use of Vitamin K in Warfarin Reversal in Adult Inpatients

Purpose:

Vitamin K (phytonadione) is a commonly used first-line reversal agent for vitamin K antagonist (VKA) therapy in patients presenting with a supratherapeutic international normalized ratio (INR) with or without significant bleeding or in patients with a therapeutic INR in need of surgery. The purpose of this study was to determine the impact of education on the appropriate use of vitamin K for VKA reversal.

Methods:

Data were collected on patients admitted to a community teaching hospital during February 2010 (pre-education group). These data were analyzed to determine the most common guideline deviations in vitamin K use. Following this analysis, pharmacist education took place in the form of in-service presentations; a protocol, including a guideline-based dosing table, was developed to assist pharmacists in evaluating vitamin K therapy. Data were then collected on patients admitted during February 2011 (post-education group).

Results:

Forty patients and 47 vitamin K administrations were included in the pre-education group, and 34 patients and 49 vitamin K administrations were included in the post-education group. The number of patients with appropriate vitamin K administrations improved after pharmacist education (25% pre-education vs 55.8% post-education; P = .01). Whereas 27.6% of individual vitamin K administrations were appropriate in the pre-education group, this increased to 63.2% in the post-education group (P = .04).

Conclusion:

Education techniques on the appropriate use of vitamin K for VKA reversal significantly improved compliance with standards of care for proper use of vitamin K. Additional education sessions are necessary to further increase compliance with standards of care and subsequently optimize patient care.     

晚发型维生素K缺乏症11例

目的 总结晚发型VitK缺乏症的诊治经验,预防本病的发生。方法 对11例晚发型VitK缺乏症临床资料进行回顾性分析。结果 11例晚发型VitK缺乏症患儿,合并颅内出血7例,痊愈5例(包括1例合并颅内出血),自动放弃治疗6例(均为合并颅内出血)。结论 补充VitK和输新鲜血应同时并重。4个月以内婴儿应积极采取预防措施。     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

维生素K对HBsAg与抗HBS结合的抑制作用

在ＲＰＨＩ试验中，将ＶｉｔＫ１或ＶｉｔＫ３预先与ＨＢｓＡｇ阳性血清作用后，再加抗ＨＢｓ单克隆抗体诊断红细胞，可见红细胞呈圆点状沉淀，提示ＨＢＳＡｇ与抗ＨＢｓ的结合受到抑制，该抑制作用呈浓度依赖性．ＲＰＨＩ试验后的抗ＨＢｓ单克隆抗体诊断红细胞，经洗涤后再与ＨＢｓＡｇ阳性血清作用，仍出现明显凝集，表明ＶｉｔＫ对ＨＢｓＡｇ与抗ＨＢｓ结合的抑制作用不是通过影响抗ＨＢｓ而产生的。     

维生素K_1联合门冬氨酸洛美沙星注射液治疗急性胃肠炎临床效果分析

目的:观察维生素K1联合门冬氨酸洛美沙星注射液治疗急性胃肠炎的临床疗效。方法:选择2012年8月—2013年10月收治的急性胃肠炎患者96例,随机分为治疗组和对照组,每组48例,其中对照组给予门冬氨酸洛美沙星注射液0.4 g加入5%葡萄糖注射液250 mL中静脉滴注,每日1次;治疗组给予维生素K180 mg联合门冬氨酸洛美沙星注射液0.4 g加入5%葡萄糖注射液250 mL中静脉滴注,每日1次,两组均为3 d一个疗程。结果:治疗组显效43例,有效3例,无效2例,显效率89.6%,总有效率95.8%;对照组显效34例,有效5例,无效9例,显效率为70.8%,总有效率81.2%,两组间比较差异有统计学意义(P<0.05)。结论:维生素K1联合门冬氨酸洛美沙星注射液治疗急性胃肠炎临床效果显著,进一步研究需大样本的临床观察。     

维生素D的代谢、与疾病的关系以及合理使用的探讨

维生素D是人体必需的脂溶性维生素,其水平受很多因素的影响,主要包括紫外线辐射、膳食补充、年龄和肥胖、种族和民族因素等。维生素D缺乏与很多疾病的发生密切相关,包括骨骼疾病、癌症、自身免疫性疾病和心血管疾病等,因此及时了解人体的维生素D的状态,实现维生素D的个体化补充具有重要的意义。     

Role of ABC transporters in trans‐epithelial transport of vitamin K antagonists

Vitamin K antagonists (VKAs) remain the oral anticoagulant of choice in venous thromboembolic disease. These drugs are characterized by a large inter‐individual variability requiring frequent dose tailoring. Genetic polymorphisms for cytochrome CYP2C9 and VKORC1 explain some of the variability, especially in warfarin and acenocoumarol responses. The aim of this study was to assess, in cell models, the role of ABC transporters in the intestinal transfer of the main coumarin derivatives (warfarin, acenocoumarol) and indanedione derivatives (phenindione, fluindione). The results show a basal to apical polarized transport for fluindione, phenindione and acenocoumarol only. Experimental studies using specific inhibitors of transport protein demonstrate the implication of MRPs and BCRP proteins and to a lesser extent P‐gp. Warfarin and acenocoumarol seem to be poor inhibitors of MRPs protein, whereas fluindione and phenindione have a slight or no effect. The regulation of the expression of ABC transporters by exposure to VKAs was also investigated in Caco‐2 cells. The expression of mRNA P‐gp, MRP1, MRP2 and BCRP was weakly or not modified after 24 h of VKAs exposure. In conclusion, the intestinal transfer of indanedione derivatives and acenocoumarol could be influenced by transport proteins of the ABC superfamily. Coumarin derivatives are poor inhibitors of these proteins and AVKs have a slight effect on the mRNA ABC transporter expression level. Copyright © 2016 John Wiley & Sons, Ltd.     

维生素 K1、酚磺乙胺与氨甲苯酸在输液中的配伍稳定性考察

目的：研究维生素K1、酚磺乙胺、氨甲苯酸与0．9％氯化钠或5％葡萄糖注射液配伍后在避光或光照条件下的稳定性。方法采用高效液相色谱法测定维生素K1、酚磺乙胺、氨甲苯酸与输液配伍后避光或光照条件下12 h内药物的含量,并观测配伍溶液的外观、pH值的变化。结果时间、光条件和输液种类均未对配伍溶液的外观性状和pH产生明显影响。在避光条件下,配伍溶液中三种药物含量均无明显变化;而光照条件下,酚磺乙胺和氨甲苯酸含量无变化,维生素K1含量显著下降。结论避光条件下,维生素K1、酚磺乙胺、氨甲苯酸在12 h内配伍稳定。     

Mean Residence Time of Oral Drugs Undergoing First-Pass and Linear Reversible Metabolism

Equations for the mean residence times in the body (MRT) and AUMC/AUC of a drug and its metabolite have been derived for an oral drug undergoing first-pass and linear reversible metabolism. The mean residence times of the drug or interconversion metabolite in the body after oral drug are described by equations which include the mean absorption time (MAT), the mean residence times of the drug or metabolite in the body after intravenous administration of the drug, the fractions of the dose entering the systemic circulation as the parent drug and metabolite, and the systemically available fractions of the drug (F _p ^p) or metabolite (F _m ^p). Similarly, the AUMC/AUC of the drug and metabolite after oral drug can be related to the MAT, ratios of the fraction of the dose entering the systemic circulation to the systemically available fraction, the first-time fractional conversion of each compound, and AUMC/AUC ratios after separate intravenous administration of each compound. The F _p ^p and F _m ^p values, in turn, are related to the first-pass availabilities of both drug and metabolite and the first-time fractional conversion fractions. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.     

Pharmacokinetics and Reversible Biotransformation of Sulfinpyrazone and Its Metabolites in Rabbits. I. Single-Dose Study

In rabbits receiving sulfmpyrazone (SO) and the sulfide metabolite (S) in four separate experiments, the biotransformation of SO into S was found to be reversible, which resulted in approximately parallel terminal disposition profiles for the three major substances in plasma, i.e., SO, S, and the p-OH-sulfide (OH-S). However, differences in disposition kinetics were observed between the intravenous and the peroral administration. The formation of OH-S was independent of both the administered compound and the administration route. The results obtained in the present studies, the previously documented enterohepatic recirculation, and the formation of S by hindgut flora may have implications for studies on sulfinpyrazone, which has been used as an antithrombotic agent.     

Pharmacokinetics and Reversible Biotransformation of Sulfinpyrazone and Its Metabolites in Rabbits. II. Multiple-Dose Study

In crossover studies rabbits were given sulfmpyrazone (SO) and its sulfide metabolite (S) perorally once daily (10 mg/kg) for 5 days. Comparison of the pharmacokinetic parameters obtained after the first and the fifth dose indicates that repeated dosing does not alter disposition kinetics of both SO and S, except that in dosing with S the observed terminal half-life for S is significantly reduced, from 4.59 ± 0.55 to 2.86 ± 0.6 hr (SD). In other studies rabbits were given higher single doses (15, 25, and 50 mg/kg) perorally and comparison was made between these dose sizes and the first dose (10 mg/kg) of multiple administration with S. Some kinetic parameters tended to be altered in a nonlinear fashion, and greater intersubject variations were observed because of the dose increase, while oxidation to SO or p-hydroxylation to OH-S from S was not significantly altered.     

Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers

1. The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n?=?8) who had received a single oral dose of 100?mg [¹⁴C]-radiolabelled BIBF 1120 administered as solution.

2. BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3?h and gMean terminal half-life was 13.7?h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution.

3. Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [¹⁴C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96?h. BIBF 1120 and metabolites were mainly excreted via faeces.

4. The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role.

     

凝血酶原复合物治疗晚发性维生素K缺乏症并颅内出血32例

目的探讨应用凝血酶原复合物治疗晚发性维生素K缺乏症并颅内出血的临床效果。方法采用回顾性分析的方法 ,对晚发性维生素K缺乏症并颅内出血患儿采用凝血酶原复合物治疗与未采用凝血酶原复合物治疗的效果进行对比分析。结果采用凝血酶原复合物治疗的晚发性维生素K缺乏症并颅内出血患儿,其出院时的情况较未采用凝血酶原复合物治疗的患儿好。对比两者纠正APTT延长的时间差,差异有统计学意义。结论使用凝血酶原复合物治疗晚发性维生素K缺乏症并颅内出血,效果良好。     

Epoxide hydrolases in the rat epididymis: possible roles in xenobiotic and endogenous fatty acid metabolism.

Epoxide hydrolases play an important role in detoxifying epoxides that arise from the metabolism of xenobiotic and endogenous compounds. Both the soluble and microsomal forms of epoxide hydrolase (sEH and mEH, respectively) have been detected in the rat testis. Because of the important role the epididymis plays in sperm maturation and protection, the present study evaluated the presence and activity of these two epoxide hydrolases in the rat epididymis. Using Western blotting, protein bands consistent in size with both mEH and sEH were detected in the caput, corpus, and cauda of the epididymis. The mEH immunoreactive bands in the epididymis ( approximately 50 kDa) were consistent with mEH detected in the liver and kidney. The sEH immunoreactive bands in the epididymis ( approximately 65 kDa) were consistent with a recombinant sEH standard and sEH detected in the liver, kidney, and testis. The presence of mEH and sEH in the epididymis was supported by observations from substrate-based enzyme assays. Results indicated that epididymal mEH can hydrolyze [(3)H]-cis-stilbene oxide to the corresponding diol at levels approximately 9% of the kidney. Epididymal sEH hydrolyzed the substrate [(3)H]-trans-diphenylpropene oxide to the corresponding diol and this activity was inhibited by cyclohexyl-dodecyl urea. Arachidonic acid epoxygenase activity was detected in epididymal S9 fractions, suggesting that fatty acid metabolism by epididymal cytochrome P450s can form epoxides that subsequently become substrates for epididymal sEH. Results from the present study indicate that the epididymis contains at least two active forms of epoxide hydrolase. The role of these enzymes in the detoxification of xenobiotic epoxides is well known, although it is unclear what cellular role they may play in the formation of biologically active metabolites in the epididymis.