Metabolic route prediction

An a priori classification of these various reactions as either toxification or detoxification is simply impossible, since each product from these various pathways may be toxic or not depending on its chemical properties and own products. Furthermore, the biological context plays a critical role [154], yet this role, best viewed as the influence of biological factors on the relative importance of competitive routes of metabolism, is often underplayed by those who venture to make predictions of metabolic outcome. Indeed, in the cascade of intertwined metabolic routes exemplified by haloalkenes, a small difference in pathway selectivity at an early metabolic crossroad may be amplified downstream, giving rise to major differences in relative levels of metabolites and overall toxicity. 

Extrapolation between species should ideally take into account metabolic routes, i.e., the absence or presence of metabolites, as well as the relative rate of formation of the individual metabolites. In PBPK models (Section 4.3.6), both aspects (nonlinearity, formation of active metabolites) are incorporated. This modeling technique uses compartments that correspond to actual tissues or tissue groups of the body. Size, blood flow, air flow, etc. are taken into account, in addition to specific compound-related parameters such as partition coefficients and metabolic rate data. Based on such studies, target-organ concentrations of active metabolites can be predicted in experimental animals and humans, thus providing the best possible basis for extrapolation (Feron et al. 1990). 

Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have... 

For all of the above reasons, it is important to predict the fate of chemicals in the environment by predicting the course of microbial metaboUsm, and it is clearly necessary to know more than whether the compound is metaboUzed but also which metabolic route or routes the degradation process follows. 

Regarding the latter, it is desirable to predict all metabolic pathways, to know which pathways might dead-end and accumulate products, and to discern between likely and unlikely pathways. By combining biodegradation route predictions with predictions of environmental mobility, ecotoxicity and human toxicity, described elsewhere in this book, we can more readily identify transformation products of most concern. 

Given the overwhelming influence of the physical properties of skin in determining bioavailabilities via the dermal route, assessment of dermal penetration is one area in metabolism and toxicology where in vitro methods can be effectively used to predict in vivo results and to screen chemicals. Apparatus and equipment exist that one can use to maintain sections of skin (obtained from euthanized animals or from human cadavers or surgical discard) for such experiments (Holland et al., 1984). These apparatus are set up to maintain the metabolic integrity of the skin sample between two reservoirs the one on the stratum comeum side, called the application reservoir and the one on the subcutaneous side, called the receptor reservoir. One simply places radiolabeled test material in the application reservoir and collects samples from the receptor fluid at various time points. 

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the absorption of di-/ -octylphthalate in humans and animals following inhalation and dermal exposure. Information on absorption in humans following oral exposure is not available. There are studies that suggest oral absorption of di-/ -octylphthalate occurs in animals (Albro and Moore 1974 Oishi 1990 Poon et al. 1995) however, quantitative information is lacking. Additional information, primarily quantitative data, on absorption of di-/ -octy lphthalate for all routes of exposure is needed to understand and predict effects. 

Validation of the Model. The Corley model was validated using chloroform data sets from oral (Brown et al. 1974a) and intraperitoneal (Ilett et al. 1973) routes of administration and from human pharmacokinetic studies (Fry et al. 1972). Metabolic rate constants obtained from the gas-uptake experiments were validated by modeling the disposition of radiolabeled chloroform in mice and rats following inhalation of chloroform at much lower doses. For the oral data set, the model accurately predicted the total amounts of chloroform metabolized for both rats and mice. 

Interroute Extrapolation. The Corley model used three routes of administration, intraperitoneal, oral and inhalation, in rats and mice to describe the disposition of chloroform. This data was validated for humans by comparing the model output using the animal data with actual human data from human oral chloroform pharmacokinetic studies. Using the human pharmacokinetic constants from the in vitro studies conducted by Corley, the model made adequate predictions of the amount of chloroform metabolized and exhaled in both males and females. 

Metabolism by the P450 system results in steady-state peak levels of a major active metabolite (desmethylazelastine), which are 20% to 50% of azelastine levels. The elimination half-life of the metabolite is predicted to be 54 hours. The major route of excretion is via feces. ... 

Absorption, Distribution, Metabolism, and Excretion. Levels of cresols in blood were obtained from a single case report of a dermally exposed human (Green 1975). Data on the toxicokinetics of cresols in animals were contained in two acute oral studies that provided only limited quantitative information on the absorption, metabolism, and excretion of cresols (Bray et al. 1950 Williams 1938). A more complete oral toxicokinetics study, in addition to studies using dermal and inhalation exposure, would provide data that could be used to develop predictive pharmacokinetic models for cresols. Inclusion of several dose levels and exposure durations in these studies would provide a more complete picture of the toxicokinetics of cresols and allow a more accurate route by route comparison, because it would allow detection of saturation effects. Studies of the tissue distribution of cresols in the body might help identify possible target organs. 

Drug distribution and elimination are important factors influencing the PK/PD relationship. Models and latest advances in dmg distribution prediction are reviewed in Chapter 9. Metabolism is a major route of elimination for xenobiotics and... 

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