Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 24 , Issue 4
Showing 1-12 articles out of 12 articles from the selected issue
Theme Article: Theme Issue on Albumins with New Functions and Clinical Applications
Editorial
Reviews
  • Teruyuki KOMATSU, Akito NAKAGAWA, Xue QU
    2009 Volume 24 Issue 4 Pages 287-299
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Human serum albumin (HSA) is a versatile protein found at high concentration in blood plasma and binds a range of insoluble endogenous and exogenous compounds. We have shown that complexation of functional molecules into HSA creates unique proteins never seen in nature. Complexing an iron-protoporphyrin IX into a genetically engineered heme pocket of recombinant HSA (rHSA) generates an artificial hemoprotein, which binds O2 reversibly in much the same way as hemoglobin. A pair of site-specific mutations, (i) introduction of a proximal histidine at the Ile-142 position and (ii) substitution of Tyr-161 with Phe or Leu, allows the heme to bind O2. Additional modification on the distal side of the heme pocket provides rHSA(triple mutant)-heme complexes with a variety of O2 binding affinity. Complexing a carboxy-C60-fullerene (CF) into HSA generates a protein photosensitizer for photodynamic cancer therapy. Energy transfer occurs from a photoexcited triplet-state of HSA-CF (HSA-3CF*) to O2, forming singlet oxygen (1O2). This protein does not show dark cytotoxicity, but induceds cell death under visible light irradiation.
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  • Ger J. van der VUSSE
    2009 Volume 24 Issue 4 Pages 300-307
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Fatty acids play critical roles in mammalian energy metabolism. Moreover, they are important substrates for the synthesis of membrane phospholipids and biologically active compounds like eicosanoids and leukotrienes. Because of their low solubility in aqueous solutions such as blood plasma and interstitial fluid, fatty acids are in need of binding proteins to increase their concentration in vascular and interstitial compartments. Albumin acts as main fatty acid binding protein in extracellular fluids. Plasma albumin possesses about 7 binding sites for fatty acids with moderate to high affinity, enhancing the concentration of fatty acids by a several orders of magnitude. Despite the high affinity of albumin for fatty acids, uptake of fatty acids by parenchymal cells such as skeletal and cardiac myocytes seems not to be hampered by albumin. In contrast, experimental findings suggest that albumin may facilitate the uptake of fatty acids by organs in need of these substrates. In the present overview the following issues will be briefly discussed: (i) transport and storage of fatty acids in the mammalian body, (ii) biosynthesis of albumin in the liver, (iii) localization and concentration of albumin in body fluids, (iv) interactions between albumin and fatty acids, (v) albumin structure and fatty acid binding sites, (vi) uptake of fatty acids by organs and roles for plasma albumin and (vii) lessons from patients and experimental animals lacking plasma albumin.
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  • Yu ISHIMA, Ulrich KRAGH-HANSEN, Toru MARUYAMA, Masaki OTAGIRI
    2009 Volume 24 Issue 4 Pages 308-317
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by rapid NO release, toxicity and induction of tolerance. Therefore, novel NO donors with better pharmacological and phamacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of S-nitrosylated human serum albumin (SNO-HSA) and that is why we are testing whether this albumin form can be used as a NO traffic protein. We have found that oleate and other endogenous ligands increase SNO-HSA formation in vitro. The cytoprotective effect of SNO-HSA in a ischemia/reperfusion model and its antiapoptotic effect on HepG2 cells treated with anti-Fas antibody were pronounced and could be enhanced by binding of oleate. The enhancement of S-transnitrosation to the HepG2 cells could be completely blocked by filipin III, a caveolae inhibitor. These findings indicate that a clinical application of SNO-HSA is expected as potent NO supplementary therapy and that fatty acids may serve as novel types of mediators for S-transnitrosation.
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  • Jan Terje ANDERSEN, Inger SANDLIE
    2009 Volume 24 Issue 4 Pages 318-332
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      The half-life of the two most abundant proteins in blood, immunoglobulin G (IgG) and serum albumin, is extraordinary (~19-23 days) compared to other circulating proteins. This phenomenon secures a broad biodistribution throughout the body of both molecules. The long half-life has made IgG the natural choice for engineering of antibody based therapeutics, while albumin is used as a fusion partner for or carrier of drugs. Remarkably, the half-life of these unrelated proteins has been shown prolonged by a receptor recycling pathway mediated by a common cell bound receptor named the neonatal Fc receptor (FcRn). This review summarizes our current understanding of FcRn function and discusses its relevance for development of new IgG and albumin based therapeutics and diagnostics.
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  • David C. GAZE
    2009 Volume 24 Issue 4 Pages 333-341
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      The diagnosis of cardiac ischemia remains a challenge in contemporary emergency medicine. A blood-borne biomarker is an attractive alternative to cardiac imaging or stress testing as it would be cheaper and logistically faster to obtain. A number of candidate biomarkers have been proposed for the detection of cardiac ischemia; however, only Ischemia Modified Albumin (IMA) has been released for clinical use. IMA is a good discriminator between ischemic and non-ischemic patients. Changes in IMA concentration have shown to occur during coronary angioplasty-induced ischemia. Clinical studies indicate that IMA appears to offer on admission an early test which can be combined with electrocardiographic findings and cardiac troponin measurements for the early exclusion of acute coronary syndrome. IMA is an independent predictor of short and long term adverse outcomes in patients with acute chest pain. However, this test is relatively new and uncertainties remain. Elevations of IMA occur in conditions other than chest pain, thus questioning its specificity. The mechanism of IMA formation and the precise entity being measured are not fully known. Nevertheless, IMA measurement remains the only current clinical biomarker which may be used for the diagnosis of patients suspected of cardiac ischemia.
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  • Stephen CURRY
    2009 Volume 24 Issue 4 Pages 342-357
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Human serum albumin (HSA) is an abundant and highly soluble plasma protein with the capacity to bind a remarkably diverse set of lipophilic anionic compounds so that it fulfils important roles in the transport of nutrients, hormones and toxins. The protein attracts great interest from the pharmaceutical industry since it can also bind a variety of drug molecules, impacting their delivery and efficacy. Our understanding of the binding and transport properties of albumin has been transformed by structural studies of the protein, in which crystallographic analysis has played a leading role. This review summarises the main insights to have accrued from this work, highlighting the significant advances that have been made but also pointing out some of the challenges ahead. Since further progress is likely to benefit from increased structural scrutiny of HSA, methodological developments instrumental to the success of crystallographic analysis of the protein are discussed in some detail.
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  • Victor Tuan Giam CHUANG, Toru MARUYAMA, Masaki OTAGIRI
    2009 Volume 24 Issue 4 Pages 358-364
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Automated high-throughput techniques have become key to improving existing as well as new techniques associated with protein binding analysis. A wide variety of methods and experimental conditions are used for estimating protein binding as well as binding affinity, such as ultrafiltration and affinity chromatography. These methods rely either on the separation of a bound and free drug for subsequent conventional analysis or change in intrinsic parameters such as conformational properties of the protein. More recently developed techniques include surface plasmon resonance and solid-phase microextraction. Photoaffinity labeling, site-directed mutagenesis and x-ray crystallography are valuable techniques to identify the locations of binding sites on a protein. A new high-throughput assay based on the distribution of a drug among plasma water, plasma proteins, and solid-supported lipid membranes (Transil) has been reported to produce valid results, even for drugs that are strongly bound to plasma proteins. This new method may be suited for examining highly lipophilic drugs that adsorb onto surfaces due to their low solubility in aqueous media. Such a method may promote drug discovery and development for high-throughput determination of protein binding.
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Original Article
Regular Articles
  • Edwin SANDANARAJ, Suman LAL, Yin Bun CHEUNG, Xiaoqiang XIANG, Ming Cha ...
    2009 Volume 24 Issue 4 Pages 365-375
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1 diplotypes, CYP2C9 and CYP2C19 variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9 and CYP2C19 polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9 and CYP2C19 pharmacogenetics. The major VKORC1 diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H*b (10%). Warfarin dose requirements were significantly lower in patients with VKORC1 H1-H1 and H1-H*a diplotypes compared to patients harboring the H1-H7 and H1-H*b diplotypes (P<0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1 mRNA compared with liver tissues carrying the H1-H7 and H1-H*b diplotypes (P=0.006). The percent variability explained by VKORC1 diplotype status was 59.1% while the CYP2C9 genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1 diplotype status, CYP2C9 genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.
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  • Yusuke TANIGAWARA, Kazutaka YOSHIHARA, Kizuku KURAMOTO, Kikuo ARAKAWA
    2009 Volume 24 Issue 4 Pages 376-388
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (Emax) of olmesartan, whereas azelnidpine Emax was independent of patient background characteristics investigated. No patient was found to have a high Emax to one agent who also had a high Emax to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.
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  • Naoe YAMANE, Tomonori TAKAMI, Zenzaburo TOZUKA, Yuichi SUGIYAMA, Akira ...
    2009 Volume 24 Issue 4 Pages 389-403
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      A sample treatment procedure and high-sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantitative determination of nicardipine in human plasma were developed for a microdose clinical trial with nicardipine, a non-radioisotope labeled drug. The calibration curve was linear in the range of 1-500 pg/mL using 1 mL of plasma. Analytical method validation for the clinical dose, for which the calibration curve was linear in the range of 0.2-100 ng/mL using 20 μL of plasma, was also conducted. Each method was successfully applied to making determinations in plasma using LC/MS/MS after administration of a microdose (100 μg) and clinical dose (20 mg) to each of six healthy volunteers. We tested new approaches in the search for metabolites in plasma after microdosing. In vitro metabolites of nicardipine were characterized using linear ion trap-fourier transform ion cyclotron resonance mass spectrometry (LIT-FTICRMS) and the nine metabolites predicted to be in plasma were analyzed using LC/MS/MS. There is a strong possibility that analysis of metabolites by LC/MS/MS may advance to utilization in microdose clinical trials with non-radioisotope labeled drugs.
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Note
  • Norie MURAYAMA, Naoki KANEKO, Kana HORIUCHI, Katsuhiro OHYAMA, Makiko ...
    2009 Volume 24 Issue 4 Pages 404-408
    Published: 2009
    Released: September 10, 2009
    JOURNALS FREE ACCESS
      Small minipigs (Bland name, Micromini Pig; registered as a novel variety of pig in the Japanese Ministry of Agriculture, Forestry and Fisheries) were developed with the aim of non-clinical pharmacological/toxicological use. They were principally mated with<10 kg body weight at 7 months-old resulting in good handling. Cytochrome P450 (P450)-and flavin-containing monooxygenases (FMO)-dependent drug oxidation activity of liver microsomes prepared from male Microminipigs (8 months-old) was compared with that for pooled dogs, monkeys, and humans. High P450 2D-dependent bufuralol 1′-hydroxylation and FMO-dependent benzydamine N-oxygenation activity was observed in liver microsomes from Microminipigs. Typical P450 1A, 2B, 2C, 2E, and 3A-dependent drug oxidation activity was also seen in Microminipigs. However, occasional differences might give undetected low P450 2A-dependent coumarin 7-hydroxylation in Microminipigs at 8-months-old, in contrast to liver microsomes from one 10-days-old Microminipis and commercially available pooled minipigs which had low but detectable coumarin 7-hydroxylation activity. The present results suggest that there is some overlap in Microminipig and human P450 substrate specificity. These findings should provide important information for greater understanding of drug metabolism in Microminipigs, as an experimental animal model for non-clinical use.
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