Drug biotransformation renal

Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e.g., bile, sweat, lungs, etc.). Most drugs follow first-order elimination rates. Figures l-MOa and 1-1-lOb compare zero- and first-order elimination, and Figure 1-1-11 demonstrates how the t, and the theoretical zero time plasma concentration (C°) can be graphically determined. Two important relationships are dose = x C° and t, = 0.7/k (k = the first-order rate constant of elimination). 

Biotransformation involves the chemical alteration of a molecule to alter its effects. This often terminates the pharmacological effects of a drug, but active metabolites are produced in some cases. Biotransformation also changes the ease with which a drug is eliminated. This involves conversion of the drug to a more hydrophilic metabolite that enhances renal excretion. Although this process pertains to most drugs, it probably... 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

In the oral cavity, drug metabolism occurs in mucosal epithelial cells, microorganisms, and enzymes in the saliva metabolism also takes place in renal and hepatic tissue once the drug is swallowed. Although biotransformation of agents in the oral cavity is potentially an important aspect of reducing effective drug concentra-... 

The oximes contain a quaternary ammonium group that contributes to their acidity and their strong binding to the inhibited enzyme. This appears to be a key structural element in known reactivators, but it tends to make them poorly soluble in lipids. Practically, this means that the drugs are slowly absorbed from the gastrointestinal tract, have difficulty entering the brain, do not easily enter hepatic cells to be biotransformed, and are not reabsorbed from the renal tubular urine. 

Small molecules are eliminated from the body largely by means of drug metabolism enzymes in the liver and other tissues and by urinary excretion. Large molecules are also eliminated by renal and hepatic mechanisms. Proteins that are less than 40 to 50 kDa are cleared by renal filtration with little or no tubular reabsorption. Larger proteins are less likely to be filtered but may be subject to phagocytosis in hepa-tocytes and Kupfer cells in the liver. Protein biotransformation—denaturation, proteolysis, and oxidative metabolism—is also important. 

Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions (Figure 4-1). 

Renal failure will result in a diminished elimination of drugs that are primarily secreted, such as penicillins and aminoglycosides, and therefore in a longer half-life of the drug (45). Likewise, liver disease may result in a capacity-limited biotransformation, and consequently in a slower elimination of the drug. Bacterial pneumonia in calves may also result in increased serum oxytetracycline concentrations, a condition that can cause prolonged elimination (46). 

Regardless of the type of chemical reaction used, biotransformation also helps in metabolite excretion from the body by creating a more polar compound.18,53 60 After one or more of the reactions just described occurs, the remaining drug metabolite usually has a greater tendency to be ionized in the body s fluids. The ionized metabolite is more water soluble, thus becoming transported more easily in the bloodstream to the kidneys. Upon reaching the kidneys, the polar metabolite can be excreted from the body in the urine. The contribution of biotransformation toward renal excretion is discussed in a later section. 

In terms of drug elimination from the entire body, systemic clearance is calculated as the sum of all individual clearances from all organs and tissues (i.e., systemic CL = hepatic CL + renal CL + lung CL, and so on). Note that the elimination of the drug includes the combined processes of drug loss from the body (excretion) as well as inactivation of the drug through biotransformation.7 58 60... 

The elimination half-life of canrenone ranges from approximately 12 to 20 hours, depending upon the spironolactone dose administered [83], Metabolites of spironolactone are primarily eliminated renally, with only minimal biliary excretion. Little to no parent drug is recoverable in the urine, reflecting the complete biotransformation of the compound [72,74,83]. 

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