Absorption in vivo studies

K. Masumoto, K. Matsumoto, A. Yoshida, S. Hayashi, N. Nambu, and T. Nagai, In vitro dissolution profile and in vivo absorption study of sustained-release tablets containing chlorpheniramine maleate with water-insoluble glycan, Chem. Pharm. Bull., 32 3720 (1984). 

Various in vitro and in vivo methods have been used to predict drug absorption including Caco-2 cells, in situ intestinal permeability, whole-animal studies, and more recently chromatographic methods. Compared with in vivo absorption studies, evaluation of intestinal permeability in vitro requires less compound is relatively easy to study, often avoiding complicated surgery is rapid and can allow a wider variety of variables to be controlled. ... 

Yokoyama et al (10) calculated the thermodynamic values of forms I and II of acetohexamide from solubility measurements. The transition temperature and the heat of transition were 154 and 230 cal/mole, respectively. It is found that the polymorphic forms of acetohexamide did not affect its bioavailability when In vivo absorption studies of form I II were carried out in beagle dogs. The preparation of four crystalline modifications of acetohexamide was reported (11). Their thermograms, IR spectra. X-ray diffraction and solubility are also reported. Two of the forms reverted to the most stable form on storage in solution. 

Jerry, N., Anitha, Y., Sharma, C.P., Sony, P. In vivo absorption studies from an oral delivery system. Drug Deliv., 8, 19, 2001. 

In Vivo Absorption Studies IVIale Wister albino rats, 270 - 310 g, were fasted for 2k h prior to drug administration. Ketoprofen powder or its physical mixture with methyl-3-CD (molar ratio l l) was freshly suspended in distilled water and administrated- into the stomach of a rat through a sonde at a dose of 25 mg/kg (ketoprofen) in a constant volume of 5 ml/kg. Blood samples were obtained from the femoral artery via a cannula and immediately centrifuged at 3000 rpm to obtain plasma samples. The concentration of ketoprofen in plasma was determined... 

Jerry N, Anitha Y, Sharma CP, Sony P. In vivo absorption studies of insuhn from an oral dehvery system. DrugDeliv. 2001 8(l) 19-23. 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

The importance of drug ionization using cell-based methods such as Caco-2 in the in vitro prediction of in vivo absorption was discussed [45]. It was observed that when the apical pH used in Caco-2 studies was lowered from 7.4 to 6.0 a better correlation was obtained with in vivo data, demonstrating that careful selection of experimental conditions in vitro is crucial to produce a reUable model. Studies with Caco-2 monolayers also suggested that the ionic species might contribute considerably to overall drug transport [46]. 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

Those aspects critical to the in vivo bioavailability of the product and routine control tests proposed to ensure that the product has consistent bioavailability from batch to batch. Where a product has low in vivo absorption, the evidence should be discussed and a conclusion reached as to whether this is due to intrinsic properties of the active ingredient(s) or whether it is related to the properties of the dosage form concerned. In the case of products intended to have a nonsystemic effect, the potential for systemic absorption may need to be considered. This may involve specific studies to determine the levels of the active ingredient(s) in the blood, plasma, urine, or feces and a discussion of the clinical significance of those results. 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Dissolution is also used to identify bioavailability (BA) problems and to assess the need for further BE studies relative to scale-up and post-approval Changes (SUPAC), where it functions as a signal of bioinequivalence. In vitro dissolution studies for all product formulations investigated (including prototype formulations) are encouraged, particularly if in vivo absorption characteristics can be defined for the different product formulations. With such efforts, it may be possible to achieve an in vitro/in vivo correlation. When an in vitro correlation or association is available, the in vitro test can serve not only as a quality control (QC) specification for the manufacturing process, but also as an indicator of in vivo product performance. 

Experiments in this study, done exclusively with midge larvae, include 1) 24-hr toxicity data for representative insecticides, with and without synergists 2) in vivo absorptive uptake and metabolic studies of aldrin and dieldrin, with and without piperonyl butoxide (PBO) 3) body depuration rate (loss to water) for dieldrin 4) determination of optimal in vitro... 

In-Vivo Absorption and breaking strength retention studies. For comparing PDS monofilament in-vivo properties with copolymeric fibers, a second 90/10 PDO/glycolide copolymer (II-A) was prepared and processed following similar schemes to those used for copolymer II. 

Ethylene oxide sterilized laonofilaments of copolymer II-A and a poly(p-dioxanone) were compared in terms of their in-vivo absorption and BSR (breaking strength retention) profiles. The BSR and absorption studies were conducted in rats according to the procedures described elsewhere. The comparative data of these studies are given in Table V. 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

The interstitial fluid content of the skin is higher than in the subcutaneous fat layer and normal fluid movement is intrinsically finked to lymphatic drainage as governed by mechanical stresses of the tissue. A model of temporal profiles of pressure, stress, and convective ISF velocity has been developed based on hydraulic conductivity, overall fluid drainage (lymphatic function and capillary absorption), and elasticity of the tissue.34 Measurements on excised tissue and in vivo measurement on the one-dimensional rat tail have defined bulk average values for key parameters of the model and the hydration dependence of the hydraulic flow conductivity. Numerous in vivo characterization studies with nanoparticles and vaccines are currently underway, so a more detailed understanding of the interstitial/lymphatic system will likely be forthcoming. 

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