In-vivo Pharmacokinetics Research Articles

Abstract 871: Dual inhibition of PI3K and Erk1/2 shows synergy and efficacy in human tumor cells, either by using drug combinations or novel dual PI3K/Erk inhibitors

Abstract The Ras/Raf/Mek/Erk and the PI3K/Akt signaling pathways are frequently deregulated in cancer due to activation of upstream receptors, decreased expression of tumor suppressors like PTEN or activating mutations of Ras, B-Raf or PI3K. Several clinical studies with kinase inhibitors targeting single members of the Ras/Raf/Mek/Erk or the PI3K/Akt pathway are ongoing. However, preclinical and clinical trials indicated limited success by single pathway inhibition and different resistance mechanisms were defined. Further clinical trials with drug combinations of Ras/Raf/Mek/Erk and PI3K/Akt suppressors have been initiated, suggesting a more favorable outcome than targeting only one single pathway, Ras/Raf/Mek/Erk or PI3K/Akt. We performed in-vitro combination experiments with Raf, Mek or Erk inhibitors and PI3K or Akt inhibitors in several human tumor cell lines. Strong synergy was achieved with various combinations including the Mek inhibitor CI-1040 and the PI3K inhibitor GDC-0941 (CI = 0.17) or the Erk inhibitor AEZS-131 and the PI3K inhibitor D-117073 (CI = 0.23) in A549 cells. Also Raf inhibitors like Sorafenib and Zelboraf were combined with different PI3K inhibitors, resulting in synergistic anti-proliferative activity. Due to the attractiveness of parallel inhibition of the Ras/Raf/Mek/Erk and PI3K/Akt pathways, we developed AEZS-136 that concurrently inhibits Erk1/2 (IC50 ∼ 50nM) and PI3K (IC50 ∼ 100nM) by an ATP competitive mode of action. Derivatives of the dual PI3K/Erk inhibitor were co-crystallized with Erk2 and PI3Kα enabling an optimization process by SAR driven medicinal chemistry. The anti-proliferative efficacy of AEZS-136 was evaluated in more than 40 human tumor cell lines and physico-chemical as well as in-vitro ADMET properties were widely assessed. Furthermore, the in-vivo pharmacokinetics and anti-tumor efficacy was explored. AEZS-136 was well tolerated and showed dose dependent inhibition of human colon tumor growth of up to 74% in a Hct116 mouse model. Here we present the concept of dual targeting of the Ras/Raf/Mek/Erk and the PI3K/Akt pathways, either by using drug combinations or our novel dual PI3K/Erk inhibitor. AEZS-136 is a small molecule in preclinical development showing a uniquely advantageous kinase inhibition profile. Broad clinical anti-tumor activity is expected for AEZS-136 in tumors with deregulated Ras/Raf/Mek/Erk and PI3K-Akt signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 871. doi:1538-7445.AM2012-871

Novel interpenetrated polymer network microbeads of natural polysaccharides for modified release of water soluble drug: in-vitro and in-vivo evaluation

The objective of this work was to prepare novel interpenetrating polymer network (IPN) microbeads of tamarind seed polysaccharide and sodium alginate for controlled release of the water soluble drug, diltiazem hydrochloride. The diltiazem-Indion 254(®) (a cation exchange resin) complex was prepared and the resulting complex was entrapped within IPN microbeads prepared by ionotropic gelation and covalent crosslinking. Microbeads were characterized by scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction and Fourier transform infrared spectroscopy (FTIR) analyses, and evaluated for swelling, in-vitro release and preclinical pharmacokinetics. The unformulated drug showed complete dissolution within 60min, while drug release from diltiazem-ion-exchange resin complex was extended for 2.5h but IPN microbeads extended the release for longer period. The ionically crosslinked microbeads released the drug for 6h, while dual crosslinked microbeads extended the release for 9h. The microbeads containing a higher amount of glutaraldehyde released the drug very slowly. The results of in-vivo pharmacokinetics of pure drug and drug-loaded IPN microbeads showed that the microbeads demonstrated prolonged release supporting the findings of in-vitro studies. Prepared IPN microbeads showed prolonged in-vitro and in-vivo release for diltiazem, indicating that this IPN would be a versatile delivery system for water soluble drugs.

Active Tumor Targeting of Nanomaterials Using Folic Acid, Transferrin and Integrin Receptors

Folic acid, transferrin and integrin alpha v beta 3 (αvβ3) receptors are overexpressed in various cancer cell lines. Ligands having high affinity for these receptors are often conjugated to nanocarriers to facilitate the tumor localization of therapeutic agents. In this review the use of these ligands for targeted delivery using liposomes, dendrimers and (N-(2-hydroxypropyl) methacrylamide) (HPMA) copolymers is discussed. Emphasis is placed on discussing drug delivery systems that have been optimized for in-vitro binding as well as in-vivo pharmacokinetics. Our aim is to understand the various factors influencing the targeting ability of nanocarriers.

Study of the effective dose of a topical antifungal agent, omoconazole nitrate, on the basis of percutaneous pharmacokinetics in guinea-pigs and mice.

The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis. The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used. These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.

In-vitro and in-vivo characterization of a buprenorphine delivery system

Buprenorphine is a mu-opioid receptor partial agonist with enhanced safety and comparable efficacy to methadone for treatment of opioid dependence. The sublingual formulation of buprenorphine, approved for treatment of opioid dependence, produces variable buprenorphine blood levels and requires frequent dosing that limits patient compliance. To achieve stable buprenorphine levels that may improve patient outcome, an implantable sustained buprenorphine delivery system was developed. Each implant consists of ethylene vinyl acetate copolymer and 90 mg buprenorphine HCl, and measures 26 mm in length and 2.4 mm in diameter. Steady-state release in-vitro was 0.5 mg/implant/day. In-vivo pharmacokinetics and safety were examined for up to 52 weeks in beagle dogs receiving 8, 16 or 24 subcutaneous implants. Plasma buprenorphine concentrations correlated with the number of implants administered. Peak buprenorphine concentrations were generally reached within 24 h after implantation. Steady-state plasma levels were attained between 3 and 8 weeks, and were maintained for study duration, with a calculated mean release rate of 0.14+/-0.04 mg/implant/day. There were no test-article-related adverse effects. This delivery system can provide long-term stable systemic buprenorphine levels, and may increase patient compliance, thereby improving outcome for opioid-dependent patients.

Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats

There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg(-1) per week) or as a single dose injection (20 mg kg(-1)). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameterto correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin.

Liposomally targeted cytotoxic drugs for the treatment of cancer

Phospholipid spherules composed of lipid bilayer membranes entrapping a central aqueous core were first described more than 30 years ago (Bangham et al 1965). The term liposome was coined in 1968 (Sessa & Weissmann 1968) and the first suggestions that these vesicles might have potential as vehicles for targeted drug delivery for a range of diseases, including cancer, appeared shortly afterwards (Gregoriades et al 1974; Gregoriades 1976a, b). However, the process of turning this expectation into a clinical reality has suffered a number of setbacks and has taken more than a quarter of a century. In the process, new types of liposomes with favourable in-vivo pharmacokinetics and biodistribution patterns have been generated (Lasic & Papahadjopoulos 1995). Many of these preparations have been subjected to extensive examination and an increasing number of agents have entered clinical trials. In this review, we will trace the development of those liposomes that are currently undergoing (or are about to undergo) clinical evaluation.

Polymeric nanoparticles as an oral delivery system for biocontrol agents for the brushtail possum (Trichosurus vulpecula)

AIM: To investigate polymeric nanoparticles as an oral delivery system for protein biocontrol agents for control of the brushtail possum, Trichosurus vulpecula. METHODS: Insulin-loaded poly(ethyl 2-cyanoacrylate) (PECA) nanoparticles were prepared using interfacial polymerisation, and characterised for size, zeta potential, and efficiency of encapsulation of insulin. In-vitro release of insulin-loaded PECA nanoparticles was quantified using reverse-phase highpressure liquid chromatography (HPLC). The in-vivo pharmacokinetics of insulin in PECA nanoparticles was investigated following I/V administration, and when injected directly into the caecum alone or in conjunction with the permeation enhancer EDTA. Blood samples were collected at intervals from −5 to 180 minutes, and the concentration of insulin in plasma was quantified using a radioimmunoassay (RIA) validated for possum plasma. RESULTS: Poly(ethyl 2-cyanoacrylate) nanoparticles were produced with a uniform particle size of 200–300 nm, and the mean entrapment of insulin was 78%. In-vitro release of insulin from the PECA nanoparticles was controlled, although incomplete, and approximately 30% of the insulin remained entrapped. The bioavailability of insulin when administered in a PECA nanoparticulate formulation injected directly into the caecum was <1%, and was not increased by addition of the permeation enhancer. CONCLUSIONS: The nanoparticulate formulations investigated as part of this study resulted in low bioavailability of the peptide insulin in the brushtail possum.

Emodin Studies on Pharmacokinetics and Distribution in Rat Liver after Polygonum cuspidatum Sieb. et Zucc. Extract Administration

Abstract A rapid, sensitive and selective high-performance liquid chromatography method (HPLC) has been developed and validated to investigate the pharmacokinetics and distribution profile of emodin in rats after taking Polygonum cuspidatum Sieb.et Zucc. and to reflect Polygonum cuspidatum Sieb.et Zucc.'s in-vivo changing rule in rats. The emodin in the biosamples was tested, and the plasma emodin concentration-time curve and liver emodin concentration-time curve were plotted. The pharmacokinetic model of emodin fitted to open two-compartment model in rat. The emodin was rapidly absorbed with peak plasma concentration occurring at 9 min after administration of the extract. The Cmax was 3.973±0.535 μg/mL, and its calculated elimination half life was 11 h. The emodin concentration-time curve in the liver showed that Tmax and Cmax were 10 min and 9.654±1.41 μg/g, respectively. The emodin concentrations both in the plasma and liver decreased notably, within 24 h after administration. The emodin in Polygonum cuspidatum Sieb.et Zucc. was absorbed rapidly into the blood and distributed quickly into the liver of the rat. The results of this study may provide reference to in-vivo pharmacokinetics study of anthraquinones, which are emodin analogs and help explain the material base of the pharmacologic effect of Polygonum cuspidatum Sieb.et Zucc.

The use of the suicide CYP450 inhibitor ABT for distinguishing absorption and metabolism processes in in-vivo pharmacokinetic screens

Since drug candidates with low oral systemic exposure may be due to either or both absorption and metabolism factors, determining what factors limit the oral systemic exposure is not always obvious in a single in-vivo pharmacokinetic (PK) assay. A rapid rat in-vivo PK screen where the oxidative drug metabolism has been attenuated using the suicide CYP450 inhibitor aminobenzotriazole (ABT) is described. We have shown that the roles of absorption and metabolism for drug candidates with low oral systemic exposure can be determined by comparing the PK parameters of drug candidates orally administered to non-treated and ABT-treated rats. Propranolol, metoprolol and climetidine are used as model drugs. Propranolol and metoprolol have low oral systemic exposures in rats primarily due to metabolism factors while the oral systemic exposure of climetidine is high in rats. For propranolol and metoprolol, large increases in the systemic exposure of these drugs were observed between non-treated and ABT-treated rats. ABT appeared not to increase or decrease significantly the rate and extent of absorption or metabolism of cimetidine since that oral systemic exposure of non-treated and ABT-treated rats did not significantly change. These experiments suggest that for drug candidates with low systemic exposures in rats an observation of no change in the oral systemic exposure in ABT-treated rats when compared to the non-treated rats imply that absorption (or formulation) factors limit the systemic exposure of the drug while an increase in the systemic exposure in ABT-treated rats imply that metabolism factors limit the systemic exposure. Due to the ease of preparing and interpreting PK data from ABT-treated rats, is suggested that this assay could be used as an alternative to in vivo cannulation assays.

Allometric scaling of pharmacokinetic parameters in drug discovery: can human CL, Vss and t1/2 be predicted from in-vivo rat data?

In a drug discovery environment, reasonable go/no-go human in-vivo pharmacokinetic (PK) decisions must be made in a timely manner with a minimum amount of animal in-vivo or in-vitro data. We have investigated the accuracy of the in-vivo correlation between rat and human for the prediction of the total systemic clearance (CL), the volume of distribution at steady state (Vss), and the half-life (t1/2) using simple allometric scaling techniques. We have shown, using a large diverse set of drugs, that a fixed exponent allometric scaling approach can be used to predict human in-vivo PK parameters CL, Vss and t(1/2) solely from rat in-vivo PK data with acceptable accuracy for making go/no-go decisions in drug discovery. Human in-vivo PK predictions can be obtained using the simple allometric scaling relationships CL(Human) approximately = 40 CL(Rat) (L/hr), Vss(Human) approximately = 200 Vss(Rat) (L), and t1/2(Human) approximately = 4 t1/2(Rat) (hr). The average fold error for human CL predictions for N = 176 drugs was 2.25 with 79% of the drugs having a fold error less than 3. The average fold error for human Vss predictions for N = 144 drugs was 1.85 with 84% of the drugs having a fold error less than 3. The average fold error for human t1/2 predictions for N = 145 drugs was 2.05 with 76% of the drugs having a fold error less than 3. Using these simple allometric relationships, the sorting of drug candidates into a low/medium/high/very high human classification scheme was also possible from rat data. Since these simple allometric relationships between rat and human CL, Vss, and t1/2 are reasonably accurate, easy to remember and simple to calculate, these equations should be useful for making early go/no-go in-vivo human PK decisions for drug discovery candidates.

In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

Aspects of In-Vivo Pharmacokinetics of Ethanol

Aspects of In-Vivo Pharmacokinetics of Ethanol

Aspects of In-Vivo Pharmacokinetics of Ethanol

Aspects of In-Vivo Pharmacokinetics of Ethanol

In-vivo Ocular Microdialysis to Monitor Ocularly Applied Cyclosporin in the Anterior Chamber of Rabbits

The purpose of this study was to prepare an ophthalmic cyclosporin formulation, reducing its local irritation, and to monitor the concentration of ocularly applied cyclosporin in an anterior chamber using in-vivo ocular microdialysis in rabbits. Oily solutions or emulsions of cyclosporin (0.4 and 2% w/v) were prepared from Sandimmun (10% w/v oral preparation of cyclosporin) by diluting with olive oil or Intralipos (20% w/v injectable lipid emulsion), respectively. These formulations were topically applied to the eye of the rabbit and monitored by ocular microdialysis. The highest concentration of cyclosporin in the anterior chamber was observed within 10 min of ocular application of drug formulations, followed by a gradual decrease until 120 min. The use of emulsion for topical cyclosporin did not influence the pharmacokinetics of cyclosporin in the anterior chamber compared with the application of its oily solution. The therapeutic level of cyclosporin (greater than 80 ng mL−1) in the anterior chamber could be attained by the 0.4% formulation. Local irritation after the instillation of the cyclosporin formulations was examined using the blinking count method. The irritation of the emulsion was significantly diminished compared with the oily solution. The present study suggests that 0.4% (w/v) cyclosporin emulsion is a suitable preparation as the ophthalmic formulation, and that microdialysis is a suitable method for investigation of in-vivo ocular drug pharmacokinetics.

Studies of the adduct formed on interacting cisplatin with human apotransferrin: Synthesis, in vitro binding kinetics, in vivo pharmacokinetics and biodistribution in the rat.

F040 STUDIES OF THE ADDUCT FORMED ON INTERACTING CISPLATIN WITH HUMAN APOTRANSFERRIN: SYNTHESIS, IN VITRO BINDING KINETICS, IN VIVO PHARMACOKINETICS AND BIODISTRIBUTION IN THE RAT. J.D. Hoeschelea L.R. Whitfield,b W.R. Leopold,b W. McNally,b J. Nawrocki,b J. Phillips,C a Department of Chemistry, University of Michigan, Ann Arbor, MI, 48109-I 055 b Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105 and C Cancer Therapy and Research Foundation of South Texas, San Antonio, TX 78229. Transferrins are glycoproteins which are important in the cellular transport and storage of iron and other metal ions into cells [ 11. Since many tumor cells overproduce transferrin receptors, an attractive concept is to consider using transferrin as a delivery system to target cancer drugs specifically to tumor cells. We have undertaken a test of this concept using a cisplatin(cisPt)apotransferrin(aTf) adduct which was (1) synthesized, isolated (via dialysis), and analyzed via 1g5mPt radioactivity, (2) tested in vivo for antitumor activity vs implanted M5076 ovarian sarcoma tumors in the mouse, and (3) used to study the pharmacokinetic and biodistribution properties in vivo for comparison with those of cisplatin. The results and conclusions are as follows: (1) CisPt reacts with human aTf with an apparent first-order rate constant of -2x10-5 set-l. Since this rate constant is comparable to that for the aquation reaction of cisPt, it is likely that the reaction proceeds via an aquation intermediate. (2) The isolated adduct is non-stoichiometric with an approximate empirical formula of Pt~.410_75Tf. (A Pt/Tf ratio of 1.8-2.0 would be expected if the cisPt-aTf reaction went to completion and cisPt occupied both available Fe@) binding sites.) (3) The cisPt-aTf adduct is inactive against murine M5076 ovarian sarcoma over a wide range of dose levels (799-3318 mg as Tf/Kg body weight), indicating that active cisPt is not being delivered via the adduct. (4) The cisPtaTf adduct is a unique entity which exhibits pharmacokinetic and biodistribution properties distinctly different from those of cispt.

In-vivo microdialysis sampling in pharmacokinetic studies

Microdialysis sampling is a powerful technique for studying in-vivo pharmacokinetics and the metabolism of drugs. Introduction of a dialysis membrane into a blood-vessel or tissue allows the collection of small molecules from the extracellular space. Several calibration methods are discussed as well as the analytical challenges involved with this technique. The application to blood and muscle are demonstrated for studies of the in-vivo pharmacokinetics and biotransformation Of L-DOPA in dog.

Pharmacokinetic and In-Vitro Characteristics of Sustained Release Verapamil Products

AbstractThe in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan (V) and Isoptin SR (ISR), were compared. The effect of food on V was also examined in a separate study with conventional Isoptin (I) as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for ISR and 8 hours for V. The extended in-vitro profile of V versus ISR was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for V and ISR respectively. In a second pharmacokinetic study the rate and extent of absorption of verapamil from V was shown to be unaffected by food.

Receptor-mediated radiopharmaceuticals

The development of radiotracers with defined affinities for specific receptor systems is a potentially useful approach to the design of radiopharmaceuticals for nuclear medicine. Radiolabelled ligands, such as hormones and neurotransmitters, are being synthesized and evaluated as diagnostic tools for diseases which can be characterized either by changes in receptor concentration or by novel receptor expression. Since the utility of a radiopharmaceutical is dependent upon the achievement of adequate ratios of target to nontarget accumulation of radioactivity, design of radiotracers via the receptor approach attempts to exploit those systems in which receptor is present in significantly higher concentration at potential target sites such as tumors. Receptor-mediated radiotracers are also currently being used in animal models to investigate the normal tissue distribution of drug and hormone receptors and the in-vivo pharmacokinetics of receptor binding. The successful development of receptor-avid radiopharmaceuticals will depend on the ability to synthesize ligands of high specific radioactivity which retain the high affinity and binding specificity for the receptor after radiolabelling.

Proliferative parameters relevant to cancer therapy.

It is becoming increasingly widely accepted that besides a better knowledge of the in-vivo pharmacokinetics and of the effective tissue concentrations of therapeutic agents, reliable data on the proliferative properties of both neoplastic tissues and critical normal cell systems (i.e. stem cells of the bone marrow and intestinal epithelium, and the cell populations involved in the immune response) may be indispensable for the design of more rational schemes of tumor therapy. The steady growth of the body of information on the proliferative characteristics of mammalian cell systems during past years has supported and given direction to this trend. However, the initial rapid advances in this field have also uncovered new and unexpected difficulties, whose solution will require new efforts on both the conceptual and the methodological side (6, 13–15, 21, 25).KeywordsCell Cycle PhaseSulfur MustardCell Cycle TimeProliferative PropertyProliferative FractionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.