Metabolism and elimination drugs

At birth, term infants can metabolize and eliminate drugs. For most patients these systems did not function during fetal life and therefore even at birth are not very efficient. Table 6.1 outlines the time required for maturation of some of the systems used in drug absorption and elimination. Table 6.2 lists other factors that alter drug disposition in newborns. The ability to absorb and eliminate drugs increases slowly over the first month of life. 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

After an intravenous bolus dose, serum concentrations decrease as if the drug were being injected into a central compartment that not only metabolizes and eliminates drug but also distributes drug to one or more other compartments. Of these multicompartment models, the two-compartment model is encountered most commonly (see Fig. 5-5). After an intravenous bolus injection, serum concentrations decrease in two distinct phases described by the equation ... 

One man s meat is another man s poison. Simple and common medicines such as penicillin and aspirin are notorious for their ability to cause adverse reactions in a minority of patients. If their side-effects vary from individual to individual, might their main effects not also be expected to do so, and is this not something which we should expect of all medicines. Patients come in different ages, sexes and sizes. They differ with respect to their ability to absorb, metabolize and eliminate drugs. They may have differing co-morbidity. Some may lack enzymes which most possess. The more we learn about genetics, the more we identify factors which can have an effect on health. Patients also differ with respect to lifestyles and severity of disease. These are all reasons to suspect that, when it comes to therapy, one size fits all may be an inappropriate philosophy. 

The standard dose of a drug derives from studies in healthy volunteers and patients with normal capacity to metabolize and eliminate drugs [78]. However, the effective dose maybe different from patient to patient. Pathologic conditions... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Penicillamine Adsorption, Distribution, Metabolism, and Elimination Profile Table 1. Penicillamine drug interactions... 

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

Drug-drug interactions are often more problematic with carbamazepine than other mood stabilizers. Carbamazepine increases the activity of certain liver enzymes. Because these enzymes metabolize and eliminate medications and other substances introduced to the body, carbamazepine therapy can decrease the blood level and thereby reduce the effectiveness of itself (a phenomenon called autoinduction) and other medications that are metabolized by these enzymes. It is not unusual to find that the dose of carbamazepine must be increased after several weeks, because it has increased its own elimination. Other medications may likewise be less effective. Of particular concern are the oral contraceptives, Depo-Provera, and protease inhibitors used for the treatment of HI V+ patients. Oral contraceptives often require an increase in dose. 

The benzodiazepines that have been most commonly marketed as sedative-hypnotics include temazepam (Restoril), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and triazolam (Halcion). Of these five, temazepam is the most easily metabolized and eliminated. Therefore, temazepam is preferred for elderly and medically ill patients to minimize the risk of drug accumulation. 

Bullock P, Larsen D, Press R, Wehrman T, Martin DE. (2008) The absorption, distribution, metabolism and elimination of bevirimat in rats. Biopharm Drug Dispos 29 396-405. 

In general, a poor nutritional state and a diseased state can be expected to influence the sensitivity to chemicals. This is of special concern when the target organ of the toxic effect is affected by the disease, or when the metabolism and elimination are disturbed. Also lifestyle factors such as alcohol, tobacco smoke, and drugs may modify the toxic responses of chemicals. 

Metabolism/Excretion- Atazanavir is extensively metabolized and eliminated primarily by the liver. Following a single 400 mg dose of atazanavir, 79% and 13% was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the... 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

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