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Hepatic Clearance (hepatic + clearance)
Selected AbstractsA cremophor-free formulation for tanespimycin (17-AAG) using PEO- b -PDLLA micelles: Characterization and pharmacokinetics in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2009May P. Xiong Abstract Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L -lactide) (PEO- b -PDLLA). Dynamic light scattering revealed PEO- b -PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO- b -PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CLrenal) increased and the hepatic clearance (CLhepatic) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t1/2) of the drug in serum and 1.2-fold increase in t1/2 of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (Vd) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO- b -PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1577,1586, 2009 [source] Biodistribution characteristics of all- trans retinoic acid incorporated in liposomes and polymeric micelles following intravenous administrationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2005Shigeru Kawakami Abstract The aim of this study was to investigate the biodistribution characteristics of all- trans retinoic acid (ATRA) incorporated in liposomes and polymeric micelles following intravenous administration. [3H] ATRA were incorporated in distearoylphosphatidylcholine (DSPC)/cholesterol (6:4) liposomes. Two types of block copolymers, poly (ethylene glycol)-b-poly-(aspartic acid) derivatives with benzyl (Bz-75) groups, were synthesized to prepare the polymeric micelles for [3H]ATRA incorporation. ATRA were dissolved in mouse serum to analyze their inherent distribution. After intravenous administration, the blood concentration of [3H] ATRA in liposomes and polymeric micelles (Bz-75) was higher than that of inherent [3H]ATRA, suggesting that liposomes and polymeric micelles (Bz-75) control the distribution of ATRA. Pharmacokinetic analysis demonstrated that [3H]ATRA incorporated in polymeric micelles (Bz-75) exhibit the largest AUCblood and lowest hepatic clearance of ATRA, suggesting that polymeric micelles (Bz-75) are an effective ATRA carrier system for acute promyelocytic leukemia (APL) therapy. These results have potential implications for the design of ATRA carriers for APL patients. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2606,2615, 2005 [source] Interaction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahuricaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KAZUHISA ISHIHARA The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2,- and 16,-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg,1 dose. 6,-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg,1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg,1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg,1), but not low dose (0.3 g kg,1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg,1. It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs. [source] Whole Blood Manganese Concentrations in Dogs with Congenital Portosystemic ShuntsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2010A.G. Gow Background: Manganese (Mn) is an essential mineral that is a cofactor for many enzymes required in the synthesis of proteins, carbohydrates, and lipids. Because hepatic clearance is essential in Mn homeostasis, conditions in humans resulting in hepatic insufficiency including cirrhosis and both acquired and congenital portosystemic shunting have been reported to result in increased blood Mn concentrations and increased Mn content in the central nervous system. Because Mn toxicity causes neurologic disturbances, increased Mn concentrations have been implicated in the pathogenesis of hepatic encephalopathy. Hypotheses: Dogs with congenital portosystemic shunts (cPSS) have significantly higher whole blood Mn concentrations than do healthy dogs or those with nonhepatic illnesses. Animals: Eighteen dogs with cPSS, 26 dogs with nonhepatic illnesses, and 14 healthy dogs. Methods: Whole blood Mn was measured by graphite furnace atomic absorption spectrometry. The diagnosis of cPSS was made by ultrasonography or during celiotomy either by visual inspection of a shunting vessel or portovenography. Results: Dogs with a cPSS had significantly higher whole blood Mn concentrations than did healthy dogs and dogs with nonhepatic illnesses. Whole blood Mn concentrations were not significantly different between healthy dogs and dogs with nonhepatic illnesses. Conclusion and Clinical Importance: Dogs with a cPSS have significantly increased whole blood Mn concentrations. Additional studies are warranted to investigate the role of Mn in cPSS-associated hepatic encephalopathy. [source] WST11, A Novel Water-soluble Bacteriochlorophyll Derivative; Cellular Uptake, Pharmacokinetics, Biodistribution and Vascular-targeted Photodynamic Activity Using Melanoma Tumors as a Model,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Ohad Mazor ABSTRACT WST11 is a novel negatively charged water-soluble palladiumbacteriochlorophyll derivative that was developed for vascular-targeted photodynamic therapy (VTP) in our laboratory. The in vitro results suggest that WST11 cellular uptake, clearance and phototoxicity are mediated by serum albumin trafficking. In vivo, WST11 was found to clear rapidly from the circulation (t1/2= 1.65 min) after intravenous bolus injection in the mouse, whereas a longer clearance time (t1/2= 7.5 min) was noted in rats after 20 min of infusion. The biodistribution of WST11 in mouse tissues indicates hepatic clearance (t1/2= 20 min), with minor (kidney, lung and spleen) or no intermediary accumulation in other tissues. As soon as 1 h after injection, WST11 had nearly cleared from the body of the mouse, except for a temporal accumulation in the lungs from which it cleared within 40 min. On the basis of these results, we set the VTP protocol for a short illumination period (5 min), delivered immediately after WST11 injection. On subjecting M2R melanoma xenografts to WST11-VTP, we achieved 100% tumor flattening at all doses and a 70% cure with 9 mg/kg and a light exposure dose of 100 mW/cm2. These results provide direct evidence that WST11 is an effective agent for VTP and provide guidelines for further development of new candidates. [source] New method for the simultaneous estimation of intrinsic hepatic clearance and protein binding by matrix inhibitionBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2008Takahide Uchimura Abstract The purpose of this study was to develop a method for estimating the hepatic clearance (CLh) without using a protein binding test. This method allows the simultaneous evaluation of the intrinsic hepatic clearance (CLint) with a correction for microsomal binding, and the free fraction in the serum (fu). It uses the decrease in metabolic velocity achieved by decreasing the free fraction of a compound in the incubation mixture (fuinc) by the addition of serum, and by changing the microsomal protein concentration. This method is denoted as the ,matrix inhibition method', because it uses the inhibition of the metabolic velocity by the incubation matrix. The metabolic rates of eight compounds (diazepam, imipramine, warfarin, and compounds A,E) were evaluated under several incubation conditions using rat serum and microsomes. The correlation of CLint evaluated using the method and using equilibrium dialysis after the CLint was corrected for microsomal binding was r,=,0.968. The correlation of fu,·,CLint was r,=,0.996. Although the method required a high enough fu and fumicrosomes difference among the reaction conditions for each compound, it could evaluate CLint and fu simultaneously and easily by adding additional reaction conditions to the metabolic stability tests performed in ADME screening. Copyright © 2007 John Wiley & Sons, Ltd. [source] In vitro,in vivo correlations for drugs eliminated by glucuronidation: Investigations with the model substrate zidovudineBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2002Sam Boase Aims, To investigate the effects of incubation conditions on the kinetic constants for zidovudine (AZT) glucuronidation by human liver microsomes, and whether microsomal intrinsic clearance (CLint) derived for the various conditions predicted hepatic AZT clearance by glucuronidation (CLH) in vivo. Methods, The effects of incubation constituents, particularly buffer type (phosphate, Tris) and activators (Brij58, alamethacin, UDP-N-acetylglucosamine (UDP-NAcG)), on the kinetics of AZT glucuronidation by human liver microsomes was investigated. AZT glucuronide (AZTG) formation by microsomal incubations was quantified by h.p.l.c. Microsomal CLint values determined for the various experimental conditions were extrapolated to a whole organ CLint and these data were used to calculate in vivo CLH using the well-stirred, parallel tube and dispersion models. Results, Mean CLint values for Brij58 activated microsomes in both phosphate (3.66 ± 1.40 µl min,1 mg,1, 95% CI 1.92, 5.39) and Tris (3.79 ± 0.74 µl min,1 mg,1, 95% CI 2.87, 4.71) buffers were higher (P < 0.05) than the respective values for native microsomes (1.04 ± 0.42, 95% CI 0.53, 1.56 and 1.37 ± 0.30 µl min,1 mg,1, 95% CI 1.00, 1.73). Extrapolation of the microsomal data to a whole organ CLint and substitution of these values in the expressions for the well-stirred, parallel tube and dispersion models underestimated the known in vivo blood AZT clearance by glucuronidation by 6.5- to 23-fold (3.61,12.71 l h,1vs 82 l h,1). There was no significant difference in the CLH predicted by each of the models for each set of conditions. A wide range of incubation constituents and conditions were subsequently investigated to assess their effects on GAZT formation, including alamethacin, UDP-NAcG, MgCl2, d -saccharic acid 1,4-lactone, ATP, GTP, and buffer pH and ionic strength. Of these, only decreasing the phosphate buffer concentration from 0.1 m to 0.02 m for Brij58 activated microsomes substantially increased the rate of GAZT formation, but the extrapolated CLH determined for this condition still underestimated known AZT glucuronidation clearance by more than 4-fold. AZT was shown not to bind nonspecifically to microsomes. Analysis of published data for other glucuronidated drugs confirmed a trend for microsomal CLint to underestimate in vivo CLH. Conclusions, AZT glucuronidation kinetics by human liver microsomes are markedly dependent on incubation conditions, and there is a need for interlaboratory standardization. Extrapolation of in vitro CLint underestimates in vivo hepatic clearance of drugs eliminated by glucuronidation. [source] Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitusJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2010Joo H. Lee Abstract Objectives In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration,time curve from time zero to time infinity (AUC) of metabolites, AUCmetabolite/AUCparent drug ratios, or the time-averaged nonrenal and total body clearances (CLNR and CL, respectively) of parent drugs as reported in the literature have been compared. Key findings After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CLint) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. Summary Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans. [source] | ||||||||||