Metabolism clearance and

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. 

Grime K, Riley RJ. The impact of in vitro binding on in vitro - in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions. Curr Drug Metab 2006 7(3) 251-264. 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

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. 

Total body clearance occurs by metabolic clearance and by renal excretion. The excretion of propylene glycol is species dependent. Humans clear 45% of propylene glycol via kidney, and in dogs, up to 88%. In rats and rabbits, very little of the parent compound is excreted by the kidney until saturation of metabolism occurs. Inhibition of alcohol dehydrogenase by pyrazole increases urinary excretion of propylene glycol to 75% in rats. 

VOCs are also capable of inducing P450s and alter their, and/or other VOCs , metabolism. Eor example, repeated exposure to styrene, increased metabolic clearance, and isopropanol has been shown to potentiate CCI4 hepatotoxicity. 

The general formula for barbiturates is given in Table 34-10. Any change in the constituents at position five that confers an increase in lipid solubility typically results in increased onset of action, decreased duration of action, and increased potency. Moreover an increase in hydrophobic properties also leads to more rapid and extensive hepatic metabolic clearance and thus to decreased urinary efimina-tion of an unchanged drug. 

Figure 49-12 Secretion, metabolism, clearance, and circulating forms of PTH. Both intact PTH and inactive fragments containing the middle and carboxyl (C)-terminal amino acids are secreted by the parathyroid glands.These inactive fragments are also produced by peripheral metabolism of intact PTH by the liver and kidneys. Carboxyl fragments are cleared by the kidneys by glomerular filtration.The half-life and concentration of intact hormone are small compared with those of inactive fragments. (From Endres DB, Villanueva R, Sharp CF jr. Singer FR. Measurement of parathyroid hormone. Endocrinol Metab Clin North Am 1989 18 611-29.)...

Fortunately the following advances permitted the development of noncompetitive methods for intact PTH (1) the determination of the amino acid sequence of human (h)PTH (2) increased understanding of the secretion, metabolism, clearance, and circulating forms of PTH and (3) the synthesis of hPTH, fragments of hPTH, and analogues of fragments for use as immunogens, tracers, and cahbrators, for characterization of antiserum and antibody specificity, and for affinity purification of antibodies. 

Worboys PD, Bradbury A, Houston JB (1997) Kinetics of drug metabolism in rat liver slices. III. Relationship between metabolic clearance and slice uptake rate. Drug Metab Dispos 25(4) 460 67... 

Wang et al. (2004b) then used the Starcevic et al. method to determine T metabolic clearance and production rates in normal men by stable isotope dilution and LC-MS-MS, to assess the influence of ethnicity and age. Subjects underwent a constant infusion of ds-T, serum (73-T concentrations were measured by LC-MS-MS and serum total T (= T + ds-T) was measured by RIA. There were no ethnic differences. Values were lower in older than younger men. This is the first report of the use of LC-MS-MS to quantitate labeled and unlabeled analogs of an anabolic androgenic steroid in a clearance study. The amount of... 

Wang, C., Catlin, D.H., Starcevic, B., Leung, A., DiStefano, E., Lucas, G., Hull, L. and Swerdloff, R.S. (2004b). Testosterone metabolic clearance and production rates determined by stable isotope dilution/tandem mass spectrometry in normal men influence of ethnicity and age. J. Clin. Endocrinol. Metab., 89, 2936-2941. 

Although of questionable relevance for determining or assessing a PEL for JP-8, oral-toxicity studies with fuels have the advantage of administering the sample without prior fractionation of components. However, other factors related to fractional absorption, oral uptake rates,metabolic clearance, and tissue storage of the individual components lead to differential systemic doses of individual components that might influence toxicity. 

The total organ clearance (e.g., liver) will depend upon the intrinsic clearance (e.g., metabolic clearance) and the unbound fraction of the drug, fy. 

Propofol is chiefly eliminated by hepatic conjugation to inactive metabolites, which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Following an IV bolus dose, plasma levels initially decline rapidly due to both high metabolic clearance and rapid drug distribution into tissues. Distribution accounts for about half of this decline following a bolus of propofol. 

Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. About 50% of chloramphenicol is bound to plasma proteins this is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dose adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. Drug administration after hemodialysis minimizes this effect. Variabihty in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug levels. 

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... 

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