Rate of metabolism

PCBs and dioxins are well known for their ability to induce certain iso-enzymes of P450 in the mammalian liver. Some of these iso-enzymes are involved in the metabolism of steroids, and it is possible that changes in rates of metabolism might disturb hormone levels. 

FIGURE 11.3 One-way ANOVA (analysis of variance). One-way analysis of variance of basal rates of metabolism in melanophores (as measured by spontaneous dispersion of pigment due to G,.-protein activation) for four experiments. Cells were transiently transfected with cDNA for human calcitonin receptor (8 j-ig/ml) on four separate occasions to induce constitutive receptor activity. The means of the four basal readings for the cells for each experiment (see Table 11.4) are shown in the histogram (with standard errors). The one-way analysis of variance is used to determine whether there is a significant effect of test occasion (any one of the four experiments is different with respect to level of constitutive activity). 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

Looking at the foregoing results overall, the rates of loss in vivo are related to the rates of metabolism in vitro, measured or estimated. As with the OC insecticides, problems of persistence are associated with compounds that are not readily metabolized, for example, 2,2, 4,4, 5,5 -HCB in the foregoing examples. For further discussion of the dependence of elimination of lipophilic xenobiotics on metabolism, see Walker (1981). 

FIGURE 20 Rate of metabolism of PCL and its metabolites, determined from measurement of carbon-14 in the excreta and exhaled air of rats after implantation (s.c.) of the low molecular weight polymer. (From Ref. 53.)... 

Yin H, Anders MW, Korzekwa KR, Higgins L, Thummel KE, Kharasch ED, et al. Designing safer chemicals predicting the rates of metabolism of halogenated alkanes. Proc Natl Acad Sci USA 1995 92 11076-80. 

Calorimetry shows that the rates of metabolism of plant tissues vary widely with species, with cell types, and with environmental conditions. This provides a means of exploring the mechanisms by which various agents influence the health of a plant community. Studies are being done on beneficial agents such as growth promoters and detrimental ones such as atmospheric pollutants. For example, a correlation has been found between the metabolic heat rates and the extent of damage to pine needles by ozone. 

Sato et al. (1991) expanded their earlier PBPK model to account for differences in body weight, body fat content, and sex and applied it to predicting the effect of these factors on trichloroethylene metabolism and excretion. Their model consisted of seven compartments (lung, vessel rich tissue, vessel poor tissue, muscle, fat tissue, gastrointestinal system, and hepatic system) and made various assumptions about the metabolic pathways considered. First-order Michaelis-Menten kinetics were assumed for simplicity, and the first metabolic product was assumed to be chloral hydrate, which was then converted to TCA and trichloroethanol. Further assumptions were that metabolism was limited to the hepatic compartment and that tissue and organ volumes were related to body weight. The metabolic parameters, (the scaling constant for the maximum rate of metabolism) and (the Michaelis constant), were those determined for trichloroethylene in a study by Koizumi (1989) and are presented in Table 2-3. 

Carbamazepine is a potent inducer of hepatic microsomal enzymes. Not only does it increase the rate of metabolism for many other drugs, it increases the rate of its own metabolism. Hepatic enzymes become maximally induced over several weeks, necessitating a small initial dose of carbamazepine that... 

Polymorphic metabolism Genetically determined rates of metabolism (fast vs. slow) by selected isozymes of cytochrome P-450 drug-metabolizing enzymes. 

The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during en-terohepatic recirculation may have altered systemic availability in children up to approximately 3 years of age because of delayed maturation of conjugation. 

Tissue ischemia. When blood flow to a tissue is decreased or interrupted, the tissue becomes painful within a few minutes. In fact, the greater the rate of metabolism in the tissue, the more rapid is the onset of pain. The causes of pain due to tissue ischemia include ... 

Muscle spasm. The pain induced by muscle spasm results partially from the direct effect of tissue distortion on mechanical nociceptors. Muscle spasm also causes tissue ischemia. The increased muscle tension compresses blood vessels and decreases blood flow. Furthermore, the increased rate of metabolism associated with the spasm exacerbates the ischemia. As discussed earlier, ischemia leads to stimulation of polymodal nociceptors. 

No mortality was found in any embryo exposed to the controls. On the contrary, all the embryos exposed to the non-diluted samples of penta-, octa-, and deca-BDE commercial mixtures were dead after 24 h (Fig. 10). When the untreated PBDEs samples were diluted at 50%, a gradient of toxicity was observed penta > octa > deca. After dilution at 5%, no embryos exposed to untreated samples were dead. In agreement with our results, it has been demonstrated that the toxicity of deca-BDE is commonly lower than for octa- and penta-BDE commercial products exposures with mammalian models [64]. The different toxicity found in mammalian models and also in zebrafish should be related to the higher accumulation of lower brominated congeners in the body, because of their greater partitioning and retention in lipid-rich tissues and lower rates of metabolism and elimination in relation to deca-BDE. 

UDP-glucuronyltransferases catalyze the addition of glucuronic acid onto phenol, hydroxyl and carboxylic acid functions of molecules. They are expressed in many tissues of the body, including the liver and intestine [2-5], Microsomes from human intestines have been shown to metabolize UDP-glucuronyltransferase substrates including p-nitrophenol [6], 1-naphthol, morphine, and ethinylestradiol [4]. The relative rates of metabolism of these substrates in liver and intestinal microsomes are shown in Table 13.1. 

Overall, the human intestine is capable of metabolizing UDP-glucuronyltransferase substrates, although the rates of metabolism are between 5- and 10-fold lower than those observed in human liver microsomes. However, the presence of a metabolic capacity towards UDP-glucuronyltransferase substrates at the level of the enterocyte can exert a significant gut wall first-pass extraction on oral administration. 

Overall, the rates of sulfation in the intestine tend to be higher than the liver (up to 10-fold). In addition, for (+)-terbutaline, the relative rates of metabolism are reduced at sites lower down the GIT (i.e., activity values of 1195, 415 and 268 pmol min-1 mg 1 in the duodenum, ileum and colon, respectively). Thus, the intestine represents a considerable barrier to the oral bioavailability of sulfotrans-ferase substrate drugs. 

The metabolism of several CYP3A4 substrates in microsomes from the upper small intestine has been compared with liver microsomal metabolism. The results are summarized in Table 13.3. Thus, microsomes from the human upper small intestine can metabolize CYP3A4 substrates at rates approaching those found in human liver microsomes. However, the rate of metabolism in intestinal microsomes can be highly variable (8-fold for sirolimus [17] and 18- to 29-fold for midazolam [19]). 

This has been confirmed in activity studies where the rates of metabolism of midazolam [19] and erythromycin [14] have been studied in microsomes from... 

It is important to remember that absolute oral bioavailability is a function of both absorption and first-pass metabolism. Therefore, a linear approach to predicting absolute oral bioavailability based on a single parameter, such as rate or extent of absorption (fraction of dose absorbed or estimated dose absorbed) or the rate of metabolism (microsomal or hepatic intrinsic clearance), may result in an inaccu-... 

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