In vivo data

Another nucleoside analogue belonging to the same class as lamivudine is tel-bivudine. Clinical resistance to telbivudine has to be studied in more detail, but the first in vivo data and several in vitro results suggest that tebivudine s resistance profile is quite similar to that of lamivudine (Lok et al. 2007). 

To further investigate the role of the liver in brevetoxin metabolism, PbTx-3 was studied in the isolated perfused rat liver model (27, 28). Radiolabeled PbTx-3 was added to the reservoir of a recirculating system and allowed to mix thoroughly with the perfusate. Steady-state conditions were reached within 20 min. At steady-state, 55-65% of the delivered PbTx-3 was metabolized and/or extracted by the liver 26% remained in the effluent perfusate. Under a constant liver perfusion rate of 4 ml/min, the measured clearance rate was 0.11 ml/min/g liver. The calculated extraction ratio of 0.55 was in excellent agreement with the in vivo data. Radioactivity in the bile accounted for 7% of the total radiolabel perfused through the liver. PbTx-3 was metabolized and eliminated into bile as parent toxin plus four more-polar metabolites (Figure 3). Preliminary results of samples stained with 4-(p-nitrobenzyl)-pyridine (29) indicated the most polar metabolite was an epoxide. 

Such models can be used to perform in silico experiments, for example by monitoring the response of a system or its components to a defined intervention. Model output - predictions of biological behaviour - is then validated against in vitro or in vivo data from the real world. 

MESSINA M J, PERSKY V, SETCHELL K D R, BARNES s (1994) Soy intake aud cancer risk a review of the in vitro and in vivo data. Butr Cancer. 21 113-31. 

POLKOWSKI K and mazurek a p (2000) Biological properties of genistein. A review of in vitro and in vivo data. Acta Pol Pharm. 57 (2) 135-55. 

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]. 

Lewandowski TA, Bartell SM, Ponce RA, Faustman EM. 2001. Mechanism-based comparison of in vitro and in vivo data on methyhnercury toxicity in developing rodents. Toxicologist 60 258. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Table 6.38 PYRAZOLINE DERIVATIVES AND RIMONABANT (382) - IN VIVO DATA...

The rat has been previously used as a model animal for in vivo study of naltrexone (72). As shown in Figures 10 and 11, after an initial burst, the naltrexone plasma levels were 1.03 0.52 ng/mL/mg injected conjugate for P(HPG/LEU)-naltrexone-14-acetate and 0.70 0.39 ng/mL/mg injected conjugate for P(HPG/LEU)-naltrexone-3-acetate for 30 days. From these in vivo data, to achieve a similar plasma level in human, a subcutaneous injection dose of 100 to 500 mg can be predicted assuming that the volume of distribution of naltrexone per kilogram of body weight is of the same magnitude for both rats and humans. 

JE Polli. Analysis of in vitro - in vivo data. In GL Amidon, JR Robinson, RL Williams, eds. Scientific Foundations for Regulating Drug Products. Arlington, VA AAPS Press, 1997, pp 335-351. 

The performance of this system is shown in Figure 17 for the release of nifedipine from the GITS system [47], The reproducibility of the release rates is remarkable. Also note that the fractions released over time from three separate doses are basically superimposable. It should also be noted that these systems have an inherent delay in the onset of drug delivery which arises from the time required to build up a sufficient hydrostatic pressure to permit release of the gel that is formed within the tablet during delivery. Figure 18 shows the comparison of the in vitro and in vivo cumulative fraction released for the 30 mg system. Clearly, the in vitro performance is mirrored in the in vivo data. 

Walter, E., Kissel, T., Reers, M., Dickneite, G., Hoffmann, D., Stuber, W., Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data, Pharm. Res. 1995, 32, 360-365. 

Overall, in this chapter we have attempted to emphasize the need for more in vivo studies to be conducted to clarify the dynamic interplay between mechanisms of drug transport and metabolism in the human intestine under in vivo conditions. There is also a need to develop additional in vivo techniques for direct measurements of these processes in regions along the GI tract in humans, and to relate the findings to various physiological/pathophysiological conditions. This would clearly increase our knowledge of the mechanisms involved, and provide in vivo data to help develop and validate rapid and reliable in vitro intestinal models. 

D. K., Groothuis, G. M., Characterization of the uptake of rocuronium and digoxin in human hepatocytes carrier specificity and comparison with in vivo data, J. Pharmacol. Exp. Ther. 1998, 285, 506-510. 

The interaction between drugs in the lumen and intestinal components is generally a poorly studied area, and it is difficult based on in vivo data to discriminate such effects from other factors affecting absorption. In addition, evidence for the in vivo relevance of available in vitro methods is sparse. 

This methodology provides resolution of approximately 1 mm. Thus, not only in vitro but in vivo data from genetic knockouts and other animal models can be obtained with PET and more recently SPECT imaging [65]. 

A number of families of PTK inhibitors (tyrphostins) have shown efficacy in tissue culture as well as in vivo. A significant number of benzene malono nitriles (BMNs), which belong to the founding family of PTK inhibitors were found to possess biological activity. These include AG 490, AG 126 and AG 556 for which promising in vivo data already exist [10,11,34-37]. 

Most of the information on the metabolism of hexachloroethane has been collected by in vitro techniques using rat liver slices or rat liver microsomes. Figure 2-3 summarizes the results of these studies. The identification of tetrachloroethene and pentachloroethane as the initial metabolites of hexachloroethane metabolism in vitro agrees with in vivo data from sheep that were orally exposed to doses of 500-1,000 mg/kg hexachloroethane (Fowler 1969b). 

All in vivo data, including the human and rat absorption data used by both Egan and Zhao et al., have considerable variability. Zhao et al. comment that measurements of percent absorbed for the same molecule may vary by 30%, and that the 95% confidence interval for a prediction is approximately 30% given a model RMSE of 15%. This is approximately the same as the normal experimental error for absorption values. This means that models predicting percent absorbed have to be carefully interpreted, i.e., a prediction of 30% absorbed really means the molecule is predicted to have absorption from 15 to 45%, and that classification models should work nearly as well as regression models. 

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