The Safety Evaluation of Fluvastatin, an HMG-CoA Reductase Inhibitor, in Beagle Dogs and Rhesus Monkeys

Fluvastatin is a potent synthetic competitive inhibitor of ß-hydroxy-ß-methyl-glutaryl-coenzymeA (HMG—CoA) reductase, the rate-limiting enzyme in thebiosynthetic pathway for hepatic cholesterol synthesis. Thetherapeutic indication is reduction of elevated total and low-densitylipoprotein cholesterol levels. Results from four toxicity studiesin beagle dogs and one study in rhesus monkeys following oraladministration of fluvastatin are reported. In two 26-week dogstudies, doses were 0, 1, 8, or 48 mg/kg/day (reduced to 36mg/kg/day in Week 7) and 0, 6, 24, or 36 mg/kg/day (reducedto 30 mg/kg/day in Week 2). In a 2-year dog study, doses were0, 1, 8, or 16 mg/kg/day. Dose levels in the 26-week monkeystudy were 0, 0.6, 12, and 48 mg/kg/day (raised to 84 mg/kg/dayin Week 17 and to 108 mg/kg/day in Week 22). In these studies,evaluations included clinical and physical examinations, bodyweight and food consumption, electrocardiography, ophthalmoscopy,hematology and clinical chemistries, urinalysis, blood drugconcentration, and macroscopic and microscopic exaininationsof observed lesions and representative tissues. In the 26- and52-week dog studies and the monkey study, lenticular biochemistry,the HMG—CoA reductase activity of liver microsomes, andserum lipid concentrations were investigated. The fourth dogstudy was a single-dose toxicokinetic study in which 48 mg/kg[³H]-fluvastatin was monitored for up to 2 weeks. Sampling waslimited to ocular tissues for enzyme analysis. Doses of 24 mg/kg/daywere lethal in dogs. At lethal doses, ataxia, convulsions, fecalblood, multifocal congestion and hemorrhage, isolated foci ofmalacia in the medulla oblongata, and liver necrosis were observed.Reduced weight gain, emesis, cataracts, elevated liver enzymes,reduced cholesterol, and gallbladder inflammation with mucosalhyperplasia occurred at 8 mg/kg/day. In contrast to other HMG—CoAreductase inhibitors, fluvastatin did not cause significantcentral nervous system hemorrhage or testicular changes in dogs.Monkeys tolerated exposure to fluvastatin well with only mildgallbladder changes observed. Reduced serum cholesterol andslight hyperplasia of the gallbladder mucosa occurred in the12 and 48/84/108 mg/kg/day groups.     

Pharmacokinetics and Pharmacodynamics of CD4-Anchoring Bi-Functional Fusion Inhibitor in Monkeys

Purpose

This study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a chimeric protein, CD4-anchoring bi-functional fusion inhibitor (CD4-BFFI), in monkeys and assess the feasibility for HIV-1 treatment in humans.

Methods

The serum concentrations of CD4-BFFI and CD4 receptors were determined and modeled using a target-mediated drug disposition (TMDD) model following intravenous administration of 1 or 10 mg/kg in monkeys. In vitro CD4 internalization was examined in human peripheral blood mononuclear cells.

Results

Noncompartmental analysis showed a decrease in clearance (1.35 to 0.563 mL/h/kg) and an increase in half-lives (35 to 50 h) with increasing doses. Dose-dependent CD4 occupancy was observed. The TMDD model reasonably captured the PK/PD profiles and suggested greater degradation rate constant for the free CD4 than the bound CD4. In vitro assay showed CD4-BFFI did not reduce the internalization of cell surface CD4. The simulated serum concentrations of CD4-BFFI were 20-fold above its in vitro IC₅₀ for HIV-1 at 3 mg/kg weekly or biweekly following subcutaneous administration in humans.

Conclusions

The TMDD modeling and in vitro CD4 internalization study indicate that CD4-BFFI does not induce CD4 internalization and CD4-BFFI short half-life is likely due to normal CD4 internalization. The simulated human PK supports CD4-BFFI as a promising anti-HIV-1 agent.     

Cardiovascular Effects after Inhalation of Large Doses of Albuterol Dry Powder in Rats, Monkeys, and Dogs: A Species Comparison

Albuterol is a quickly acting ß₂-adrenergic agonistbronchodilator widely used by asthmatics. Because recent case-controlstudies have suggested a relationship between the increase inmortality of asthmatics over the past decade and the use ofß₂-adrenergic agonists in the control of asthma, concernhas developed regarding the potential cardiotoxicity of ß₂-specificadrenergic agonists, including albuterol. The aim of this investigationwas to assess the potential for cardiotoxicity of inhaled albuteroldry powder in rats, monkeys, and dogs. All species were exposedto an aerosol of albuterol 1 h per day, 7 days per week, forat least 2 weeks. Control groups were exposed to filtered conditionedair and handled in the same manner as the albuterol-exposedanimals. Plasma concentrations of albuterol confirmed systemicexposure. The daily inhaled dose received by the animals wascalculated based on measured respiratory minute volumes, publishedrespiratory tract deposition data, as well as HPLC-determinedparticle size distribution data and aerosolized albuterol concentrationsMultiples of the maximum daily clinical dose (presentation of15 µg/kg in a 70-kg human) were approximately 0.25- to2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5-to 90-fold in the dog. No findings attributed to albuterol wereobserved in the monkey. Tachycardia and transient hypokalemiaoccurred in rats at multiples of 1.5 times or greater of themaximum clinical dose. Absolute and relative heart weights increasedin rats receiving multiples of 47 times or greater of the maximumhuman dose. In the absence of histopathologic findings, theincreases in rat heart weights were considered a physiologichypertrophic response to tachycardia. In dogs tachycardia andtransient hypokalemia occurred at all doses tested. Slight tomild fibrosis in the papillary muscles of the left ventricleof the heart occurred in dogs at multiples 19 times the clinicaldose. The cardiovascular effects observed were consistent withthe known pharmacologic action of ß₂ agonists. Dueto the lack of toxicologically relevant findings in rats andmonkeys and the wide safety margin in dogs, the findings inthis study do not suggest a cardiotoxicity risk in the humanpopulation alter repeated exposures to clinical doses of albuterolcurrently used in the treatment of asthma.     

Disposition of the Aromatase Inhibitor LY56110 and Associated Induction and Inhibition Studies in Rats, Dogs, and Monkeys

Disposition of the Aromatase Inhibitor LY56110 and AssociatedInduction and Inhibition Studies in Rats, Dogs, and Monkeys.LINDSTROM, T. D., AND WHITAKER, G. W. (1987). Fundam. Appl.Toxicol. 8, 595–604. Compound LY56110 was well absorbedbut slowly excreted in the rat, dog, and monkey. Oral administrationof 5 mg/kg of [¹⁴C]LY56110 (5-bis(4-chlorophe-nyl)methylpyrimidine)to the rat, monkey, and dog resulted in a total excretion of68, 65, and 30% of the radioactivity within 5 days, respectively.Very low urinary excretion was observed in the rat and dog (2%),with fecal excretion being the predominant mode of eliminationin all three species. The plasma radioactivity half-life was49, 41, and greater than 100 hr in the rat, monkey, and dog,respectively. The plasma half-life of parent compound was 18hr in the rat and 10 hr in the dog. LY56110 accounted for only25, 12, and 1% of the plasma radioactivity area under the curvein the rat, dog, and monkey, respectively. High levels of radioactivitywere observed in the target tissues of fat, adrenals, and ovariesof rats. LY56110 induced hepatic cytochromes b₅ and P-450 andcytochrome c reductase in rats after 14 days of oral dosingat 10 mg/kg but not in monkeys after 10 days of oral dosingat 10 mg/kg. The compound was more potent than aminoglutethimideor cimetidine in inhibiting hepatic ethylmorphine and p-nitro-anisoledemethylase activity in vitro. LY56110 also inhibited ethinamate-inducedsleeping time in rats in vivo. The compound induced a reversetype I binding spectrum with rat ovarian microsomes.     

新型FXa抑制剂知非沙班采用不同溶剂口服给药对犬PK-PD的影响

目的：观察新型FXa抑制剂知非沙班采用不同溶剂口服给药对犬PK-PD的影响。方法：在离体酶活性实验中,采用生色底物法测定不同浓度的知非沙班对FXa的抑制活性,计算IC50值;在动物实验中,知非沙班分别采用0.5%的CMC-Na制备成混悬液和采用含PEG400、乙醇、水 (体积比3∶1∶1)的混合溶剂制备成溶液,对犬以1 mg?kg-1的剂量灌胃给药,分别在给药前、给药后0.5、1、2、3、4、6、9、12、15、24 h股静脉采血,分离血浆后,LC-MS/MS测定各个时间点血药浓度和药代动力学参数,生色底物法测定各时间点的FXa活性。结果：离体酶活性检测结果显示,知非沙班的IC50值11.1 nmol?L-1,表明其有良好的FXa抑制活性;动物实验结果显示,以CMC-Na为溶剂,知非沙班吸收缓慢,血药浓度低,FXa抑制活性低;以混合溶液为溶剂,知非沙班吸收迅速,血药浓度显著升高,FXa抑制活性明显增强。 结论：新型口服FXa抑制剂知非沙班使用CMC-Na和混合溶剂作为溶剂,对犬口服后的药物吸收和药效学发挥有显著的影响。     

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

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Interspecies Pharmacokinetics of a Novel Hematoregulatory Peptide (SK&F 107647) in Rats,Dogs, and Oncologic Patients

Purpose. To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. Methods. Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 ng/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). Results. In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd_ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a·W^b), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd_ss, and T_1/2 of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. Conclusions. Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.     

Subacute Toxicity of a Novel Inhibitor of Acyl-CoA: Cholesterol Acyltransferase in Beagle Dogs

PD 132301–2 is a substituted urea hypolipidemic and antiatheroscleroticagent that is a potent inhibitor of acyl-CoA:cholesterol acyltransferase(ACAT). To determine its subacute toxicity, PD 132301–2was administered orally to beagle dogs at 0, 6, 12, 25, 50,200, 400, or 800 mg/kg/day for 2 weeks. Clinicopathologic evaluationswere completed on all dogs. Liver and adrenal total and esterifiedcholesterol concentrations, adrenocorticotrophic hormone (ACTH)responsiveness, and adrenal ultrastructure were determined at0, 6, 12, and 25 mg/kg. At 12 mg/kg or greater, salivation,epiphora, conjunctivitis, emesis, anorexia or decreased foodconsumption, and soft to mucoid feces and/or diarrhea were noted.Suppression of ACTH response occurred by Day 6 at all doses.Adrenocortical degeneration and/or necrosis in zona fasciculataand reticularis was seen at all doses; adrenal free and esterifiedcholesterol were normal at 6 mg/kg and decreased at 12 and 25mg/kg. Increases in serum alanine aminotransferase (2- to 15-fold),aspartate aminotransferase (2- to 12-fold), and alkaline phosphatase(2- to 7-fold) were noted at 50 mg/kg or greater. Periportalhepatocellular hypertrophy and hypereosinophilia occurred at50 mg/kg or greater; hepatic cholesterol values were not significantlyaffected by treatment. Dose-dependent ultrastructural alterationsin adrenocortical cells included decreased numbers of mitochondriaand smooth endoplasmic reticulum profiles, qualitative and quantitativechanges in lipid globules, and increased numbers of autolysosomes.PD 132301-2 or one of its metabolites has potent adrenocorticolyticproperties and limited hepatotoxic properties by mechanism(s)that are likely independent of systemic ACAT inhibition.     

Pharmacokinetics and Tissue Disposition in Monkeys of an Antisense Oligonucleotide Inhibitor of Ha-Ras Encapsulated in Stealth Liposomes

Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.     

In Vitro Evaluation of the Plasma and Blood Compatibility of a Parenteral Formulation for Ditekiren,a Novel Renin Inhibitor Pseudopeptide

Ditekiren (U-71038; Boc-Pro-Phe-N-MeHis-Leu-[CHOHCH₂]-Val-Ile-aminomethyl)pyridine) is a potent renin inhibitor peptide and was formulated for clinical intravenous administration in acidified dextrose. This formulation of ditekiren was evaluated in vitro with human and monkey plasma as to its potential for forming a precipitate either of drug or of plasma proteins. Analysis by centrifugation showed that no drug precipitation occurred in plasma from either species at concentrations 25 times higher than anticipated in clinical studies. Results obtained by turbidimetry indicated that formulated ditekiren did not cause aggregation of human platelets or flocculation of proteins at concentrations approaching the solubility limit of the drug in plasma. Ditekiren or vehicle also caused no detectable lysis of red cells at concentrations representing 10 times the maximum clinical level. Therefore, ditekiren solutions as formulated are judged completely compatible with blood and plasma upon clinical intravenous administration.     

碳水化合物对犬体内司帕沙星药动学的影响

目的:探讨碳水化合物饮食对司帕沙星(SPFX)药动学的影响。方法:8只Beagle犬分别在空腹或碳水化合物饮食状态下单次口服SPFX胶囊10mg·kg-1,2周后交叉实验,采用高效液相色谱法测定不同时间血药浓度,用3p97软件计算二者的药动学参数并进行比较。结果:空腹和碳水化合物饮食状态下SPFX的药-时曲线符合二室模型。主要药动学参数t1/2β分别为(17.90±5.36)、(14.71±2.64)h;tmax分别为(3.28±1.32)、(3.44±0.97)h;Cmax分别为(0.70±0.19)、(0.82±0.21)μg·mL-1;AUC(0～)t分别为(11.66±3.77)、(14.65±4.24)μg·h·mL-1,两两比较均无显著性差异。结论:碳水化合物饮食对SPFX药动学参数未见明显影响。     

利福平对异烟肼在犬体内药动学的影响

目的研究利福平对异烟肼在犬体内药动学的影响。方法采用自身对照法双周期两制剂交叉设计实验方案，犬取血前3 d连续给予较大剂量的异烟肼片和利福平片，然后A组3只犬饲喂异烟肼2片（200 mg），B组3只犬饲喂异烟肼2片（200 mg）和利福平2片（300 mg），取血样进行测定［色谱柱：ZORBAX SB ODS柱（4.6 mm×250 mm，5 μm）；柱温：40 ℃；流速：1.0 mL·min-¹；进样量：20 μL；流动相：甲醇 0.02 mol·L^-1磷酸缓冲液（体积分数为2.5%，pH值为6.2）；紫外检测（λ＝268 nm）；以吡嗪酰胺为内标测定异烟肼的含量］。间隔两周后，A、B两组交叉给药，重复试验。结果异烟肼在犬体内代谢的药 时曲线下面积（AUC0→24）在不同犬间的差异有极显著性，异烟肼在不同个体间吸收与消除具明显的个体差异，但不同给药周期间差异无显著性。结论利福平和异烟肼无药物间不良交互影响，利福平对异烟肼在犬体内的药动学无明显影响。     

Effect of YM-44781, YM-44778 and YM-49598, novel tachykinin antagonists, in a drug-induced bladder contraction model

The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK(3) receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK(2) (pK(i) = 9.94 +/- 0.03) and NK(1) (pK(i) = 9.09 +/- 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK(1) (pK(i) = 8.08 +/- 0.07) and NK(2) (pK(i) = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK(2) receptor agonist, [betaAla8]neurokinin A (4-10) (10 microg x kg(-1) i.v.) was observed after intravenous administration (dose range 0.001-1 mg x kg(-1)) of YM-44781 and YM-44778 (IC(50) = 27 +/- 8 and 100 +/- 44 microg x kg(-1), respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC(50) = 11 +/- 7 microg x kg(-1)) of the contraction of the rat urinary bladder induced by challenge with the NK(1)-selective receptor agonist [Sar9,Met(O(2))11]substance P sulphone (0.3 microg x kg(-1)). YM-44781 and YM-44778 did not produce major inhibition of [Sar9,Met(O(2))11]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK(2) and NK(1) receptor antagonists, respectively, whereas YM-44778 is a nonselective NK(2)/NK(1) receptor antagonist in the drug-induced bladder contraction model.     

灯盏乙素在家犬体内的药动学研究

目的　建立高效液相色谱法测定家犬血浆中灯盏乙素的浓度 ,研究灯盏乙素在家犬体内的药动学。方法　用高效液相色谱法测定 6只家犬静脉注射灯盏乙素后不同时间血浆中灯盏乙素的浓度 ,绘制药 -时曲线 ,计算药动学参数。结果　灯盏乙素的药 -时曲线符合三室模型 ,其T1 2 pi、T1 2 α和T1 2 β分别为 1.0 5± 0 .80min ,6 .99± 2 .76min和 5 1.6 1± 2 8.78min ;Vc为 880 .1± 5 0 8.3mL ;CL为 189.6± 5 3.8mL·min- 1 ;AUC0 90 和AUC0 ∞ 分别为 5 74 .4 3± 133.95 μg·min·mL- 1 和 5 99.34± 132 .0 0 μg·min·mL- 1 。结论　静脉注射给药后 ,血浆中灯盏乙素浓度迅速下降。灯盏乙素在家犬体内消除较快 ,提示临床给药方法或给药间隔时间的确定、制剂开发的剂型选择都应该考虑其T1 2 。     

Pharmacokinetics,Mass Balance,and Induction Potential of a Novel GABA Uptake Inhibitor,CI-966 HC1, in Laboratory Animals

CI-966 exhibits anticonvulsant properties in various animal models. The drug acts by inhibiting synaptic uptake of -aminobutyric acid (GABA). Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a tmax of 0.7 hr. In rats given 5 mg/kg oral, a mean t _max of 4.0 hr was observed. Following iv administration of the same respective doses, elimination t _1/2 in dogs and rats averaged 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 was 100% in both species. Following oral dosing of [¹⁴C]CI-966 HC1 to dogs, fecal, and urinary excretion accounted for 89% and 2.3% of the ¹⁴C dose, respectively. In bile-duct cannulated rats, biliary excretion is the major elimination pathway of radioactivity (75%). Urinary and fecal excretion accounted for 4.1 and 12%, respectively. CI-966 does not induce or inhibit mouse hepatic mixed function oxidases, as determined by hexobarbital sleeping time.     

高蛋白饮食对犬体内莫昔沙星药动学的影响

目的:研究高蛋白饮食对莫昔沙星药动学的影响。方法:8只Beagle犬分别在空腹或高蛋白饮食状态下单次灌服莫昔沙星胶囊17mg·kg-1,1周后交叉实验;采用高效液相色谱法测定不同时间血药浓度,用3p97软件计算二者的药动学参数并进行比较。结果:空腹和高蛋白饮食状态下莫昔沙星的口服吸收分别符合二室、一室模型。主要药动学参数t1/2(βt1/2ke)分别为(24.89±6.77)、(10.70±3.72)h;tmax分别为(2.00±0.76)、(7.25±4.23)h;Cmax分别为(7.07±0.67)、(2.57±1.10)μg·mL-1;AUC0～t分别为(84.30±10.86)、(49.75±14.58)μg·h·mL-1。各药动学参数两两比较均有显著性差异(P<0.01)。结论:高蛋白饮食可减少莫昔沙星的吸收,加快其消除,明显影响其药动学。     

脂质饮食对诺氟沙星在Beagle犬体内药动学的影响

目的:研究脂质饮食对诺氟沙星在Beagle犬体内药动学的影响。方法:取6只Beagle犬均分为两组,分别在空腹或进食脂质状态下灌服诺氟沙星胶囊40 mg/kg,2周后两组犬交叉实验;采用高效液相色谱法测定给药前与给药后0.5、1、2、3、4、6、8、10、12、24 h的血药浓度,用3p97软件计算诺氟沙星的药动学参数。结果:诺氟沙星在Beagle犬空腹和进食脂质状态下的药-时曲线均符合一室模型;空腹和进食脂质状态下诺氟沙星的主要药动学参数分别为t1/2(3.82±1.10)、(4.30±1.78)h,tmax(0.72±0.37)、(2.94±1.12)h,cmax(0.93±0.18)、(0.92±0.43)μg/ml,AUC0-24 h(6.26±0.98)、(8.45±1.78)μg·h/ml;两种状态间比较,除tmax差异有统计学意义(P<0.01)外,其余参数差异无统计学意义(P>0.05)。结论:脂质饮食可明显延迟诺氟沙星的达峰时间。     

Relationship between Serum Concentrations, Hemodynamic Effects, and Cardiovascular Lesions in Dogs Treated with Minoxidil

The threshold hemodynamic changes associated with the cardiovascular (CV) toxicity of minoxidil (MNX) in the dog, characterized by subendocardial necrosis, right atrial hemorrhagic lesions, and coronary vascular medial hemorrhage and necrosis, have not been defined. To determine the relationship between serum concentration, hemodynamic effects [heart rate (HR) and mean arterial pressure (MAP)] and CV toxicity, groups of female Beagle dogs were treated with a continuous iv infusion of dextrose (control) or 0.05, 0.14, 0.43, 1.44, or 4.32 mg/kg/day of MNX for 3 days. Serum concentration of free MNX increased in a dose-related manner and reached steady state within 4 hr after the initiation of infusion. There was a time-dependent, apparently dose-related increase in HR at all doses. MAP was decreased at ≥0.14 mg/kg/day in a time- and dose-related manner. The doses or steady-state serum concentrations of MNX that showed no significant hemodynamic effects and CV toxicity were approximately 0.05 mg/kg or 3.0 ± 0.6 ng/ml and 0.14 mg/kg or 7.3 ± 2.0 ng/ml, respectively. CV toxicity occurred at a serum concentration of 16.6 ± 1.9 ng/ml where HR was increased by 65 ± 11 beats/min and MAP was decreased by 34 ± 2 mmHg. A serum concentration of 7.3 ± 2 ng/ml of MNX that increased HR by 47 ± 14 beats/min and decreased MAP by 17 ± 8 mmHg was not associated with CV toxicity. This study suggests that the threshold hemodynamic effects associated with the CV toxicity of MNX in the dog are a function of an increase in HR by at least 55 beats/min and a decrease in MAP by at least 30 mmHg. In conclusion, the safety margin of drugs like MNX, where the mechanisms of toxicity are known to be related to their pharmacologic effects, should be based on the ratio of the pharmacokinetically and metabolically adjusted dose/serum concentration of the drug that evokes comparable pharmacologic effects in the animal model and humans rather than on the ratio of the nontoxic dose/serum concentration in animals to the efficacious dose in humans.     

Pharmacokinetics of Vicagrel,a Promising Analog of Clopidogrel,in Rats and Beagle Dogs

The objective of this investigation was to compare the efficiency of conversion to the active metabolite (AM) from clopidogrel and vicagrel, a novel antiplatelet agent, and support the drug design rationale in the view of the pharmacokinetics. Following intravenous administration to rats, vicagrel was rapidly converted to its thiolactone intermediate (2-oxo-clopidogrel), then to the AM. The transformation efficiency of vicagrel to 2-oxo-clopidogrel was 94%, but only 13% of clopidogrel was converted to 2-oxo-clopidogrel. Compared with the clopidogrel following oral administration to rats and beagle dogs at equal molar doses, vicagrel increased the exposure to 2-oxo-clopidogrel approximately sixfold (58.6 ± 10.2 vs. 10.2 ± 6.6 µg h/L in rats, 97.1 ± 51.9 vs. 16.1 ± 3.3 µg h/L in dogs) and the exposure to the AM approximately fourfold to sixfold (59.0 ± 18.8 vs. 14.4 ± 9.6 µg h/L in rats, 635.1 ± 114.5 vs. 99.0 ± 10.3 µg h/L in dogs). The rapid and extensive conversion of vicagrel to the intermediate 2-oxo-clopidogrel by esterase instead of cytochrome P450s (CYPs) makes the novel prodrug vicagrel a promising agent to prevent platelet aggregation and overcome clopidogrel resistance and high interindividual variability due to CYP2C19 polymorphism.