Bioavailability metabolic clearance

GIT, is considered to be lost from the absorption site, as is metabolic clearance and sequestration in various cell types and membranes (72,14). It is clear from Scheme I that the relative rates of the various processes will define the bioavailable fraction of the dose and understanding those factors which control pulmonary absorption kinetics is obviously the key to enhancing bioavailability via the lung. In a recent book (75) the molecular dependence of lung binding and metabolism was considered alongside the parallel processes of absorption, clearance and dissolution in the lung (14). Some key features of this work will be repeated as it relates to the systemic delivery of polypeptides. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

Imipenem-cilastatin is only available for intramuscular or intravenous administration because oral bioavailability is poor. The enzyme, dehydropeptidase 1, present in renal tubules, converts imipenem to an inactive metabolite. To decrease metabolic clearance, imipenem is combined with cilastatin, an inhibitor of dehydropeptidase I. Additional pharmacokinetic information appears in Table 45.2. 

LMWH have higher bioavailability after subcutaneous injection than standard, heparin. LMWH binds less than heparin to plasma proteins. The clearance of LMWH is mainly renal, independent of dose and slower than metabolic clearance of heparin. 

Similarly, five days of saquinavir administration (1200 mg, t.i.d.) inhibited the metabolic clearance of intravenous and oral midazolam (106). The oral bioavailability of midazolam increased from 41% to 90%. The hepatic availability fraction was estimated to have increased from 0.64 to 0.84 and the intestinal availability fraction increased from 0.64 to about 1.0. Thus, saquinavir treatment resulted in a near complete inhibition of first-pass intestinal extraction and a lesser inhibition of hepatic extraction of midazolam. 

Thyroid hormone activity is determined predominantly by intracellular concentrations of (free) T3 in the tissues. This T3 bioavailability depends on 1) the secretion of T4 and T3 by the thyroid, 2) the conversion of T4 to T3 outside the thyroid, 3) the metabolic clearance of T3 and 4) exchange of T4 and T3 between plasma and tissues. It is the purpose of this chapter to review recent advancements in the study of the transport and metabolism of thyroid hormone. Especially the role of deiodination, conjugation and tissue uptake mechanisms will be emphasized in the regulation of thyroid hormone action. 

When the three-dimensional structure of the target is unknown, pharmacophore approaches play a predominant role among the compound selection filters that have been designed for retrieving bio-active molecules. Additional pre-filtering based upon favorable physicochemical properties necessary for, e.g., oral bioavailability, aqueous solubility, metabolic clearance, and chemical reactivity or the presence of toxic chemical groups,clearly will enhance the success rate of finding possible candidates for further optimization. 

Recently, bioavailability and clearance data obtained from a crossover study of cyclosporine kinetics before and after rifampin dosing revealed a new understanding of drug metabolism and disposition of the compound (9). Healthy volunteers were given cyclosporine, intravenously and orally, before and after CYP3A (P450 3A) enzymes were introduced by rifampin. As expected, the blood clearance and cyclosporine increased from 0.31 to 0.42 L... 

In vitro antifungal activities evaluation for sampangine metabolites demonstrated comparable activities to sampangine. However, an in vivo efficacy study revealed that SAh 2 is inactive. The antifungal activity profile of sampangine metabolites led us to conclude that metabolism per se is not the cause for the in vivo inactivity of sampangine, hence, further studies on the other pharmacokinetic parameters (bioavailability, distribution, clearance, etc.) will be necessary. 

The metabolic clearance of NCEs is most often studied with a combination of in vitro and in vivo approaches. There are several in vivo approaches that can be used to study metabolism in preclinical species and these along with in vitro results can often shed mechanistic insight into the problems associated with rapid metabolic clearance and incomplete oral bioavailability due to first-pass metabolism. Modern LC-MS/MS measurement of plasma drug eoncentrations provide a rapid tool to assess oral bioavailabihty of new eandidate compounds and allows for early definition of bioavailability problems. When bioavailability... 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

The renal clearance can be under estimated in the case of renal drug metabolism. The total drug clearance depends on bioavailability. Therefore, the most reliable estimate for the fraction eliminated by the renal route (fren) is given by the normal clearance (Clnorm) and drug clearance in case of acute and/ or chronic renal failure (Clfail), or from half-lives (Tl/2norm) and (Tl/2fail). 

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