A group of investigators is performing an experiment designed to assess genetic variability in drug biotransformation. A fixed dose of isoniazid is given to a group of volunteers, and the plasma drug concentration is measured four hours following administration of the drug. The following distribution of plasma drug concentration in these subjects is obtained. Variation of which of the following processes provides the best explanation for the shaded area of the curve?

Question

A group of investigators is performing an experiment designed to assess genetic variability in drug biotransformation.  A fixed dose of isoniazid is given to a group of volunteers, and the plasma drug concentration is measured four hours following administration of the drug.  The following distribution of plasma drug concentration in these subjects is obtained.  Variation of which of the following processes provides the best explanation for the shaded area of the curve?

Quizplus · Accepted Answer

The rate and extent of drug metabolism normally varies from person to person. These slight interpersonal variations in the ability to metabolize drugs are typically reflected graphically by a unimodal distribution, usually in the shape of a bell curve, when plasma levels of drug are measured at a fixed time following a fixed dose of drug. This is the method that was used to generate the graph given in the question stem. With most drugs, the majority of people fall within one standard deviation and 95% of people fall within two standard deviations of the population mean of plasma concentration. A single peak in this type of graph indicates that the population being tested possesses a similar genetic drug metabolizing capacity. A bimodal (discontinuous, polymorphic) curve, as shown in the question stem, results from the presence of two apparently distinct groups within the study population and suggests a pharmacogenetic polymorphism in drug metabolizing capacity. In other words, the two peaks indicate two sets of responders to the drug within the population: one that rapidly converts the drug into its metabolite (considered normals) and another that converts the drug slowly, leading to accumulation of the original drug in the plasma. Isoniazid is metabolized by acetylation to N-acetyl-isoniazid in the hepatic microsomal system by the enzyme N-acetyl transferase and is subsequently excreted in the urine. The first and second peaks in the above graph represent fast and slow acetylators, respectively. Slow acetylators of isoniazid also metabolize (acetylate) dapsone, hydralazine, and procainamide slowly, causing accumulation of these drugs as well. Slow acetylators of these drugs are at increased risk of toxic effects, while fast acetylators may require much higher therapeutic doses to achieve a therapeutic effect. (Choice A) Methylation is an important drug biotransformation method to consider when prescribing drugs such as azathioprine and 6-mercaptopurine, drugs used in the treatment of some inflammatory disorders of the bowel and skin. (Choice B) Glucuronidation is a biotransformation pathway utilized for the metabolism of numerous drugs as well as endogenous substances such as bilirubin. No bimodality has been described with this pathway, but conditions such as Gilbert syndrome involve dysfunction of the glucuronyl transferase system that can lead to toxic accumulation of some drugs. (Choice C) Hydrolysis occurs with enzymes such as esterases and amidases. Isoniazid is not metabolized by this pathway, and hydrolysis does not exhibit polymorphic metabolism. (Choice E) Amine oxidation is usually undertaken by monoamine oxidases or by cytochrome oxidative deamination. Neither process metabolizes isoniazid nor exhibits bimodality. Educational Objective: Isoniazid is metabolized by acetylation. The speed with which a patient is able to acetylate drugs depends on whether they are genetically "fast" or "slow" acetylators. The presence of fast and slow acetylators within the same population results in a bimodal distribution of the speed of isoniazid metabolism. Slow acetylators are at increased risk of adverse side effects.

A Group of Investigators Is Performing an Experiment Designed to Assess