Ocular pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-³H HCl solution (0.2%) was administered to the rabbit eye (30 μl) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180min. By 45–60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constantk _a , 0.00139 min^?1; aqueous humor elimination rate constantk ₁₀ , 0.0658min^?1; mean residence timeMRT _d , 35.6 min; apparent steadystate volume of distributionV _ss, 0.530 ml; and ocular clearanceQ _e , 14.9 =μl/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t _1/2 ) ranging from 17 to 20 hr. Over the dose range studied, no changes in , t _1/2 , or central compartment volume (Vc=1.2–1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL and steady-state volume of distribution (V _ss of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in V_ss and CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).Supported by a Grant-in-Aid from the American Heart Association, Nebraska Affiliate.     

Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone

Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p<0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p<0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p<0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.     

Pharmacokinetic and pharmacodynamic study of the combination of furosemide retard and triamterene

Summary The pharmacodynamics and pharmacokinetics of the combination of furosemide retard (30 mg)/triamterene (50 mg) were compared with furosemide (30 mg) in 18 healthy male volunteers aged 39.3±6.3 years. After the administration of furosemide the onset of its effect was very rapid, reaching a maximum between 1.5 to 3 h, and followed by rebound after 9 to 10.5 h. In contrast the combination furosemide retard/triamterene showed a protracted course with a duration of effect up to 12 h. The general effect over 12 h of the two preparations was equivalent with respect to the excretion of urine, sodium, chloride and calcium, but the combination caused significantly less excretion of potassium (p0.05) than furosemide. After a lag-phase of 33.9±5.4 min the maximum plasma concentration of furosemide was reached after 3.47±0.66 h, and the elimination half-life was approximately 2 h. After a lag-phase of 33.0±17.8 min the maximum plasma concentration of the main metabolite of triamterene, the OH-TA sulphuric acid ester, was reached after 1.7±0.59 h, and its elimination half-life amounted to 1.25±0.37 h. Because of the sustained release of furosemide from the retard-formulation, its principal pharmacokinetic parameters were better adapted to those of triamterene. The consequences were not only a protracted effect but also an improved electrolyte profile, especially with regard to reduced loss of potassium. In the case of renal insufficiency, however, the potassium level in serum might be increased to an undesirable extent.     

Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method

The effects of plasma concentration and pH on the steady-state volume of distribution, V_ss,of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100g/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the V_ss of MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p<0.05) concentration and plasma pHdependent V_ss of MTX were observed. Concentration dependence of V_ss was noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in V_ss at 1 g/ ml relative to the two higher concentrations (20 and 100 g/ ml) for dogs treated with ammonium and sodium chloride, respectively. However, V_ss of MTX at the targeted concentrations of 20 and 100 g/ml was relatively constant. Plasma pHdependence of V_ss was observed only at the plasma concentration of 1 g/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher V_ss,respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.This research was supported in part by a grant from the National Cancer Institute, CA-29754.Abstracted from a dissertation submitted in 1984 by Chung Y. Lui to the Graduate College, University of Illinois at Chicago, in partial fulfillment of Doctor of Philosophy Degree requirements.     

The combined use of high-performance liquid chromatography and radioimmunoassay for the bioanalysis of nicomorphine and its metabolites

Methods have been developed for the determination of nicomorphine using reversed-phase HPLC with UV detection; for the simultaneous assay of morphine and mononicotinoylmorphine by a coupled normal-phase HPLC-radioimmunoassay method; and for conjugates of morphine and mononicotinoylmorphine by radioimmunoassay. The methods have been evaluated and applied to a pharmacokinetic study of nicomorphine administered intramuscularly.     

5-氟尿嘧啶白及微球家兔肾动脉栓塞后体内药代动力学研究

以常规5-氟尿嘧啶(5-Fu)注射液为对照品,研究了5-Fu白及微球家兔肾动脉栓塞后体内药代动力学过程.血药5-Fu浓度采用反相高效液相色谱法,所得血药浓度数据用3P87药代动力学程序处理.实验结果5-Fu白及微球体内过程符合二室模型,t1/2a(6.27±6.10)min,t1/2β(203.6±97.5)min,Cmax(4.8±1.9)μg/ml.t1/2a,t1/2β均比注射剂明显延长(P<0.01).表明微球剂型具有靶向制剂长效、高效、低毒的特点.     

大剂量萘哌地尔在家犬体内的药物动力学

目的 :建立HPLC测定家犬血浆中萘哌地尔浓度的方法 ,研究大剂量萘哌地尔胶囊在家犬体内的药物动力学。方法 :健康家犬 5只 ,单剂量给予萘哌地尔胶囊 2 0 0mg后 ,在不同时间点从后肢静脉取血 ,血浆样品碱化后经乙醚提取 ,以乙腈 :磷酸盐缓冲液 (pH 6 .5 ) (6 0 :40 )为流动相 ,由ODSC18分析柱分离测定 ,紫外 2 30nm为检测波长 ,维拉帕米为内标。血药浓度数据用 3p97药物动力学程度处理。结果 :线性范围为 10～ 12 0 0ng·ml-1;方法回收率为98 83%～ 10 1 5 0 % ;日间RSD≤ 5 5 6 % ,日内RSD≤ 3 30 %。单剂量给予家犬萘哌地尔胶囊 2 0 0mg后 ,血药浓度随时间变化规律符合一室开放模型 ,T1/2Ke为 1 91～ 4 99h ,Tmax为 1 87～ 3 2 1h ,Cmax为 338 79～ 414 0 4ng·ml-1。结论 :本方法简便、回收率高、重现性好 ,用于大剂量萘哌地尔在动物体内的药物动力学研究 ,切实可行。     

HPLC法测定口服5—氨基水杨酸制剂后血浆和尿中的药物及其代谢物

目的建立测定血浆和尿样中5-氨基水杨酸(5-ASA)及代谢物乙酰-5-氨基水杨酸(Ac-5-ASA)浓度的HPLC方法,并进行5-ASA缓释片Pentasa的人体药动学研究.方法使用荧光检测器,以丙酰-4-氨基水杨酸为内标,用衍生化法使样品中的5-ASA丙酰化,甲醇沉淀蛋白后上清液直接进样.色谱柱为PhenomenexLunaTMC18,流动相为0.1mo1/L乙酸溶液乙腈三乙胺(460400.4,V/V/V)的混合液.测定6位健康志愿者口服1000magPentasa后血药浓度和尿药浓度.结果血浆中5-ASA及代谢物的线性范围为0.01～10μg/ml,尿样中为0.2～200μg/ml,血浆和尿中药物与代谢物的回收率在95.3%～106.2%之间,日内日间相对标准差均在052%～9.22%范围内.Pentasa口服后5-ASA和Ac-5-ASA的血药浓度在3～4h内达到峰值,分别为1.55和3.11μg/rl,AUC分别为6.90和26.32μg/(ml@h),60h内尿中排泄了口服剂量37.1%的药物.结论方法简便,灵敏度和准确度高,可用于5-ASA制剂的药物动力学研究.