In vivo absorption

Poly(lactide-coglycolide). Mixtures of lactide and glycolide monomers have been copolymerised in an effort to extend the range of polymer properties and rates of in vivo absorption. Poly(lactide- (9-glycolide) polymers undergo a simple hydrolysis degradation mechanism, which is sensitive to both pH and the presence of ensymes (32). 

Similar to pure polyglycoHc acid and pure polylactic acid, the 90 10 glycolide lactide copolymer is also weakened by gamma irradiation. The normal in vivo absorption time of about 70 days for fibrous material can be decreased to less than about 28 days by simple exposure to gamma radiation in excess of 50 kGy (5 Mrads) (35). 

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]. 

Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo importance of drug ionization in the in vitro prediction of in vivo absorption. Eur. J. Pharm. Sci. 2000, 10, 215-224. 

Permeability is a kinetic property expressed by the permeability coefficient (centimeters per second), a number indicating the rate at which molecules pass from aqueous solution across a membrane to another solution on the other side. Permeability is a molecular property used to screen for more complex absorption processes (i.e. in vitro permeabihty is measured to estimate in vivo absorption). 

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 ... 

GS Rekhi, ND Eddington, MJ Fossler, P Schwartz, LJ Lesko, LL Augsburger. Evaluation of in vitro release rate and in vivo absorption characteristics of four metoprolol tartrate immediate release tablet formulations. Pharm Devel Tech 2(1) 11-24, 1997. 

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. 

A. Kayali, Bioequivalency evaluation by the comparison of in vitro dissolution and in vivo absorption using reference equations, Eur. J. Drug Metab. Pharmacoki-net., 19, 271 (1994). 

The peculiar depression of metoprolol and quinine permeabilities in 2% DOPC (model 1.0) was not seen in the egg lecithin models. Metoprolol and quinine were significantly more permeable in the lecithins, in line with expectations based on relative octanol-water lipophilicities and relative in vivo absorptions of (3-blockers [593],... 

The 20% soy lecithin (Table 7.17) and the 2% DOPC (Table 7.15) intrinsic permeabilities may be compared in a Collander equation, as shown in Fig. 7.44. The slope of the regression line, soy versus DOPC, is greater than unity. This indicates that the soy membrane is more lipophilic than the DOPC membrane. Intrinsic permeabilities are generally higher in the soy system. Three molecules were significant outliers in the regression metoprolol, quinine, and piroxicam. Metoprolol and quinine are less permeable in the DOPC system than expected, based on their apparent relative lipophilicities and in vivo absorptions [593]. In contrast, piroxicam is more permeable in DOPC than expected based on its relative lipophilicity. With these outliers removed from the regression calculation, the statistics were impressive at r2 0.97. 

Chong, S., S. A. Dando, K. M. Soucek, and R. A. Morrison. In vitro permeability through caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system, Pharm. Res. 1996, 13, 120-123... 

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. 

There are several approaches to estimating absorption using in vitro methods, notably Caco-2 and MDCK cell-based methods or using methods that assess passive permeability, for example the parallel artificial membrane permeation assay (PAMPA) method. These are reviewed elsewhere in this book. The assays are very useful, and usually have an important role in the screening cascades for drug discovery projects. However, as discussed below, the cell-based assays are not without their drawbacks, and it is often appropriate to use ex vivo and/or in vivo absorption assays. 

Yee, S., In vitro permeability across Caco-2 cells can predict in vivo absorption in man — Fact or myth Pharm. Res. 1997, 14, 763-766. 

Fig. 1. Photophobic action spectrum (open circles, solid line) and in vivo absorption spectrum (solid line) of Rhodospirillum rubrum. Abscissa wavelength in nm Ordinates relative sensitivity and absorbance respectively (after Clayton15), from Haupt57)), modified...

When the estimates of bioavailability were compared ( ), in vivo absorption was higher than in vitro solubility for two of the foods We had expected absorption to be less than solubility due to physiological factors (lt9). Thus, this surprising result led to the reexamination of in vitro digestion conditions which is reported in this paper. 

For the quantitation of in vivo absorption of 5Ca2+, 200 jd 1 of radioactive solutions were administered by gastric gavage to male mice kept on a deionized water diet during the previous 18 hours. After 4 hours blood was obtained by axillary incision and Ca2+ was extracted with TCA and determined by liquid scintillation counting (26). 

Vashi, VI. and Meyer, M.C. (1988). Effect of pH on the in vitro dissolution and in vivo absorption of controlled-release theophylline in dogs. J. Pharm. Set 77 760-764. 

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. 

Figure 8 In vivo absorption profiles for ISMN GEOMATRIX formulations. The small-scale batches used for IVIVC development and validation are shown in panel a and the large-scale batches used for external validation are shown in panel b, with dotted line tracings for the small-scale batches. IVIVC development included two fast ( ), one medium (o), and two slow batches ( ), while external validation included two medium batches ( ).

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