Physiologically Based Pharmacokinetics of Cyclosporine A: Reevaluation of Dose–Nonlinear Kinetics in Rats

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide iv dose range (1.2–30mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CL_b ). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vu_ss ) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis–Menten kinetics, K_m 0.60 g/ml. In model-based simulations, both volume of distribution at steady state (V _ss,b ) and CL_b varied in a similar manner with dose, such that terminal t _1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood–brain barrier.     

Comparative Study of the Pharmacokinetics and Bioequivalence of Meldonium and Mildronate® Preparations

Pharmaceutical Chemistry Journal - Acomparative study of the pharmacokinetics, bioequivalence, and safety of two marketed meldonium dosage forms Meldonium Organika (meldonium, 500 mg capsules,...     

Nasal Insulin Delivery with Dimethyl-β-Cyclodextrin as an Absorption Enhancer in Rabbits: Powder More Effective than Liquid Formulations

The nasal absorption of insulin using dimethyl--cyclodextrin (DMCD) as an absorption enhancer in rabbits was studied. The nasal administration of insulin/DMCD liquid formulations did not result in significant changes in serum insulin and blood glucose concentrations. In contrast, previous experiments in rats showed that the addition of DMCD to the liquid nasal formulation resulted in an almost-complete insulin absorption, with a concomitant strong hy-poglycaemic response. Apparently, the effect of the cyclodextrin derivative on insulin absorption differs between animal species following nasal delivery of insulin/DMCD solutions. On the other hand, nasal administration of the lyophilized insulin/DMCD powder dosage form in rabbits resulted in increased serum insulin concentrations, and a maximum decrease in blood glucose of about 50%. The absolute bioavailability of the nasally administered insulin/DMCD powder was 13 ± 4%, compared to 1 ± 1% for both an insulin/ DMCD liquid and an insulin/lactose powder formulation. It is concluded that insulin powder formulations with DMCD as an absorption enhancer are much more effective than liquid formulations.     

Plasma Pharmacokinetics and Tissue Disposition of Novel Dextran–Methylprednisolone Conjugates With Peptide Linkers in Rats

The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP‐1) or five (DMP‐5) amino acids as linkers were studied in rats. Single 5‐mg/kg doses (MP equivalent) of each prodrug or MP were administered intravenously, and blood and tissue samples were collected. Prodrug and drug concentrations were quantitated using HPLC, and noncompartmental pharmacokinetic parameters were estimated. Whereas conjugation of MP with dextran in both prodrugs substantially decreased the clearance of the drug by ～200‐fold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMP‐1 in these tissues was substantially greater than that for DMP‐5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMP‐5 being twice as fast as that from DMP‐1. However, the AUCs of MP regenerated from DMP‐1 in the liver and spleen were substantially higher than those after DMP‐5. In contrast, in the kidneys, the AUC of MP regenerated from DMP‐5 was higher than that after DMP‐1 administration. These data suggest that DMP‐1 may be more suitable than DMP‐5 for targeting immunosuppression to the liver and spleen. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1626–1637, 2010     

Tissue Distribution and Anti-inflammatory Activity of DexamethasoneAcetate Incorporated In Lipid Emulsion

Objective: To study the anti-inflammatory activity and tissue distribution patterns of intravenousemulsion of dexamethasone acetate in mice. Methods: The anti-inflammatory solution for injection andLimethasone(Jepanese product) given intravenously were evaluated by using the preformed carrageenan granulomapouch method in rats. Results: The anti-inflammatory activity of dexamethasone acetate emulsion at low dose of 0.05mg.kg1 was as potent as dexamethasone sodium phosphate solution at high dose of 0.3 mg.kg1. The distributionpatterns in mice tissues of [^3H]dexamethasone acetate emulsion and [^3H]dexamethasone sodium phosphate solution inmice were markedly different. Dexamethasone acetate emulsion showed a much higher concentration in the liver,spleen, lung, and inflamed tissues, whereas dexamethasone sodium phosphate had a high concenti,mon in themuscles of vastus lateralis. These results may indicate that dexamethasone incoporated in lipid emulsion was taken upby the reticuloendothelial system and inflammatory cells much more than dexamethasone sodium phosphate solution.Conclusion: When dexamethasone acetate was incorporated in emulsion, the distribution patterns in tissues werechanged and they had a stronger anti-inflammatory activity.     

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

健康志愿者１０名，随机交叉口服硫酸吗啡控释片（ＣＲＭＳ）３０ｍｇ（３０ｍｇ×１）和硫酸吗啡普通片（ＩＲＭＳ）２０ｍｇ（１０ｍｇ×２），分别于服药前后各时点取静脉血，用ＧＣＭＳ测定血浆中吗啡含量。以药代软件程序处理，分别求得ＣＲＭＳ和ＩＲＭＳ的Ｃｍａｘ为１９．３８±３．８０和２１．２７±６．２１ｎｇ／ｍｌ；ｔｍａｘ为２．３６±０．３７ｈ和０．５５±０．１６ｈ；ｔ１／２β为３．５３±０．８７ｈ和３．０３±０．７４ｈ，曲线下面积ＡＵＣ为１４５．１５±１７．６５和９３．０８±１６．６５ｎｇ·ｈ／ｍｌ。癌症病人多次口服硫酸吗啡至稳态，ＣＲＭＳ和ＩＲＭＳ的峰浓度分别为２７．４３±０．３３ｎｇ／ｍｌ，２２．６８±０．１６ｎｇ／ｍｌ；谷浓度分别为１９．４５±１．４４ｎｇ／ｍｌ；１８．１４±０．４９ｎｇ／ｍｌ。     

Altered Tissue Distribution and Elimination of Amikacin Encapsulated in Unilamellar,Low-Clearance Liposomes (MiKasome®)

Purpose. Amikacin in small unilamellar liposomes (MiKasome^®) has prolonged plasma residence (half-life > 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system. Methods. Rats received one intravenous dose (50 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile. Results. Liposomal amikacin increased and prolonged drug exposure in all tissues. Tissue half-lives (63–465 hr) exceeded the plasma half-life (24.5 hr). Peak levels occurred within 4 hours in some tissues, but were delayed 1–3 days in spleen, liver, lungs and duodenum, demonstrating the importance of characterizing the entire tissue concentration vs. time profile for liposomal drugs. Predicted steady-state tissue concentrations for twice weekly dosing were >100 g/g. Less than half the liposomal amikacin was recovered in tissues and excreta, suggesting metabolism occurred. Amikacin was not detected in plasma ultrafiltrates. Tissue-plasma partition coefficients (0.2-0.8 in most tissues) estimated from tissue-plasma ratios at T_max were similar to those estimated from tissue AUCs. Conclusions. Low-clearance liposomal amikacin increased and prolonged drug residence in all tissues compared to conventional amikacin. The long tissue half-lives suggest liposomal amikacin is sequestered within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.     

Characterization of Silvestrol Pharmacokinetics in Mice Using Liquid Chromatography–Tandem Mass Spectrometry

A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the plant natural product silvestrol in mice, using ansamitocin P-3 as the internal standard. The method was validated in plasma with a lower limit of quantification of 1 ng/mL, accuracy ranging from 87 to 114%, and precision (coefficient of variation) below 15%. The validated method was used to characterize pharmacokinetics in C57BL/6 mice and metabolism in mouse, human and rat plasma, and liver microsomes. Mice were dosed with silvestrol formulated in hydroxypropyl-β-cyclodextrin via intravenous, intraperitoneal, and oral routes followed by blood sampling up to 24 h. Intraperitoneal systemic availability was 100%, but oral administration resulted in only 1.7% bioavailability. Gradual degradation of silvestrol was observed in mouse and human plasma, with approximately 60% of the parent drug remaining after 6 h. In rat plasma, however, silvestrol was completely converted to silvestric acid (SA) within 10 min. Evaluation in microsomes provided further evidence that the main metabolite formed was SA, which subsequently showed no cytotoxic or cytostatic activity in a silvestrol-sensitive lymphoblastic cell line. The ability of the analytical assay to measure tissue levels of silvestrol was evaluated in liver, brain, kidney, and spleen. Results indicated the method was capable of accurately measuring tissue levels of silvestrol and suggested it has a relatively low distribution to brain. Together, these data suggest an overall favorable pharmacokinetic profile of silvestrol in mice and provide crucial information for its continued development toward potential clinical testing.     

Spray-Dried and Spray-Freeze-Dried Powder Formulations of an Anti-Interleukin-4Rα Antibody for Pulmonary Delivery

Pharmaceutical Research - The therapeutic options for severe asthma are limited, and the biological therapies are all parenterally administered. The purpose of this study was to formulate a...     

Snake F(ab′)2 Antivenom from Hyperimmunized Horse: Pharmacokinetics Following Intravenous and Intramuscular Administrations in Rabbits

Purpose. The pharmacokinetics of a currently available horse F(ab)₂ antivenoms to Vipera aspis, V. ammodytes, and V. berus (Ipser Europe) and a new more purified and pasteurized preparation (SAV) was investigated in the rabbit. Methods. An immunoradiometric assay using an affinity-purified goat IgG horse F(ab)₂ specific and the same IgG labelled with iodine 125 as a tracer was developed. The limit of quantification in plasma was 0.032 µg/ml. Specificity study showed that mouse F(ab)₂ and Fab did not cross-react. Results. Pharmacokinetic analysis showed that the plasma F(ab)₂ concentration followed a biexponential decline after intravenous bolus administration with distribution and elimination half-lives of 2.66 ± 0.18 hrs and 49.69 ± 4.13 hrs, respectively. The total volume of distribution (Vdss or Vd) was between 209 and 265 ml.kg^–1 and was similar to the volume of the extracellular fluid in the rabbit (300 ml.kg^–1). Total body clearance ranged from 3.33 to 3.96 ml. h^–1 · kg^–1. After intramuscular administration which was only investigated with SAV, Tmax was 48 hrs and the absolute bioavailability was 42%. Conclusions. No difference in pharmacokinetics was observed between the two antivenom preparations following the intravenous administration. In contrast, a reduced rate and extent of absorption was shown following intramuscular administration.     

Pharmacokinetics of Pirazolac – a New Anti-Inflammatory Drug – in Human Volunteers II. Dose Linearity of Plasma Levels and Excretion

The concentration-time course of pirazolac in plasma and its urinary excretion were investigated in 6 young volunteers (3 males, 3 females) after oral administration of 50, 150, 300, 450, and 600 mg pirazolac as a crystalline suspension at weekly intervals. Only unchanged pirazolac was detected in the plasma. Maximum plasma levels and areas under the plasma level curve increased linearly with the dose. All other pharmacokinetic parameters such as t_max (3 h), oral clearance CL (0.3ml/min/kg) and terminal plasma half life t_1/2 (16–18 h) were independent of the dose. A total of 65 % of the dose was renally excreted within 72 hours mainly as pirazolac glucuronide.     

Application of the Tissue Composition–Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology

The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatology and toxicology studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clinical candidate selection. Essential input parameters in whole-body physiologically based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (V_ss). Mechanistic in vitro– and in silico–based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition–based model (TCM). Robust TCMs were initially developed for some preclinical species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biological membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting V_ss and the dermis-to-plasma partition coefficients (K_p-dermis) of 68 drugs. The prediction of K_p-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclinical species. In general, up to 86% and 100% of the predicted V_ss values are respectively within 2-fold and 3-fold errors compared to the experimentally determined values, whereas these numbers are 78% and 94% for K_p-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiologically based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclinical and clinical transdermal studies.     

Pharmacokinetic and Tissue Distribution of Orally Administered Cyclosporine A-Loaded poly(ethylene oxide)-block-Poly(ε-caprolactone) Micelles versus Sandimmune® in Rats

Pharmaceutical Research - We have previously reported on a polymeric micellar formulation of Cyclosporine A (CyA) based on poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO5K-b-PCL13K)...     

The Pharmacokinetics of Pancuronium in Infants,Children and Adults

研究观察年龄对潘库溴铵药代动力学的影响。选择２４例施择期整形外科手术的患者，根据年龄分成三组：１组为５例婴幼儿，年龄０．７５～２．９５岁；２组为１３例儿童，年龄４～１４岁；３组为６例成人，年龄１６～２７岁。静注潘库溴铵１００μｇ／ｋｇ后用改良荧光法测定其血浓度。潘库溴铵的体内过程能用二室开放模型完整描述，年龄愈小，分布容积愈大，血浆清除率愈高，潘库溴铵的血药浓度愈低。Ｖ１（中央室分布容积）、Ｖ２（周边室分布容积）、Ｖｄｓｓ（稳态分布容积）、Ｃｌ（血浆清除率）和ＡＵＣ（曲线下面积）在三组间有明显差别。１组的Ｔ１／２β和ＭＲＴ明显比２、３组长，但Ｔ１／２α和Ｋ２１在三组间无明显差别。     

Label‐Free Flow Cytometry Analysis of Subvisible Aggregates in Liquid IgG1 Antibody Formulations

The objective of this study was to characterize and quantify label‐free subvisible antibody particles in different formulations based on their size and physical properties by flow cytometry. Protein subvisible particles were prepared under various stress conditions and analyzed by applying different analytical techniques [light obscuration (LO), microflow imaging (MFI), and flow cytometry (FACS)] for the detection of aggregates. The capability of the FACS method to detect and count subvisible particles was evaluated and benchmarked against conventional techniques. FACS can analyze particles down to 500 nm reducing the gap between size‐exclusion chromatography and LO. The applied methods of FACS, LO, and MFI displayed a proportional correlation between the total particle counts, however, FACS can provide additional information on the structural characteristics of such aggregated particles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:90–99, 2014     

Quantitative Structure–Pharmacokinetics Relationships: II. A Mechanistically Based Model to Evaluate the Relationship Between Tissue Distribution Parameters and Compound Lipophilicity

The tissue-to-unbound plasma distribution coefficients (Kpus) of 14 rat tissues after iv administration of nine 5-n-alkyl-5-ethyl barbituric acids, determined in a previous study, were used to identify a model of the relationship between tissue distribution and lipophilicity of the homologs, expressed in terms of their octanol to water partition ratio, P. Based on mechanistic considerations and assumptions, the parameter model was expressed asKpu= f_W,[l + a(nP_l,)P^b], where f_W, is the tissue water content, (nP_l, ) is the binding capacity of the tissue, n is the number of the binding sites, a and b are the parameters of the relationship Ka = aP^b and Ka is the binding association constant of each tissue. The parameter model was linearized and fitted to the predetermined Kpu values, yielding correlation coefficients ranging between .940 and .997. The predictive performance of the parameter model was evaluated using a leave-one-out procedure with subsequent computation of the mean prediction error (ME = measurement of the prediction bias) and the square root of the mean squared prediction error (RMSE = measurement of the prediction accuracy). The ME varied between –22.48 and 61.14%, indicating a slight tendency for overpredicting. The RMSE was between 24.73 and 102% for the individual tissues across the different homologs; and between 28.33 and 85.2% for the individual homologs across the different tissues. The apparently high Kpu prediction errors, when translated through the low sensitivity of the barbiturate whole-body physiologically based pharmacokinetic model, established previously, leads to predicted tissue concentration–time profiles within 5 to 20% of the original ones. Therefore, it is concluded, that the identified mechanistically based model is a good predictor of the tissue-to-unbound Kpus in the rat tissues.     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ? ?11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.