Most drugs undergo chemical alteration by various bodily systems as a way to create compounds that are more easily excreted from the body. These chemical alterations occur primarily in the liver and are known as biotransformations. Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient, and is thus of interest to any provider who routinely treats patients with medication.[1][2][3][4]

Biotransformations occur by mechanisms categorized as either phase I or phase II modifications. Phase I modifications alter the chemical structure of the drug, usually by oxidation. Oxidation typically results in metabolites that still retain some of their pharmacological activity. For example, the common anxiolytic drug diazepam is transformed into desmethyldiazepam and then to oxazepam by phase I modification. Both of these metabolites produce similar physiological and psychological effects of diazepam itself. Phase II modifications involve reactions that couple the drug molecule with another molecule in a process called conjugation. Conjugation usually renders the compound pharmacologically inert and water-soluble, so that the compound can easily be excreted. Oxazepam, the active metabolite of diazepam, is conjugated with a molecule called glucuronide such that it becomes physiologically inactive and is excreted without further chemical modification.

A critical factor in drug metabolism is enzymatic catalysis of these phase I and phase II processes. The type and concentration of liver enzymes are crucial to the efficient metabolism of drugs. The most important enzymes for medical purposes are monoamine oxidase and cytochrome P450. These two enzymes are responsible for metabolizing dozens of biogenic and xenobiotic chemicals. Monoamine oxidase, as the name suggests, catalyzes processing of monoamines such as serotonin and dopamine. Monoamine oxidase inhibitors (MAOI) are used as antidepressants, as they increase concentrations of serotonin and dopamine. Cytochrome P450 catalyzes the metabolism of many psychoactive drugs, including amphetamines and opioids.

Drug metabolism can affect the plasma concentrations of drugs. There is a concern of drug-drug interactions. For example, if rifampin is taken concomitantly with imatinib, imatinib's plasma concentrations can be reduced because rifampin can induce CYP3A4 activity. Thus, imatinib's anticancer activity can be attenuated.

In any kind of pharmacological intervention, it is important to consider how and when a specific drug is eliminated from the body. Most of the time, drug clearance takes place according to first-order kinetics, in other words, the rate of clearance depends on the plasma concentration of the drug. That is, the rate of elimination is proportional to drug concentration. The rate of this form of clearance depends on the chemical in question, and is often represented by half-life. This is the amount of time it takes for 50% of the drug to be eliminated. For example, the half-life of cocaine is approximately one hour; thus, after four hours, only about 6.25% of the initial dose is present in the body.

However, the elimination of some drugs occurs at a constant rate that is independent of plasma levels. Ethanol is one example; it is eliminated at a constant rate of about 15 ml/hour regardless of the concentration in the bloodstream. This is called zero-order kinetics and occurs when enzyme binding sites are saturated at low concentrations. Kinetics are of interest in medicine because monitoring of drug concentration is often of clinical importance with many medications. An understanding of pharmacokinetics, specifically elimination, allows providers to alter therapies in a patient-specific fashion. The goal of therapy is to achieve a steady-state plasma concentration at which drug metabolism and elimination occur at equal rates.

Metabolism is a highly variable process that can be influenced by a number of factors. One major disruptor of drug metabolism is depot binding, meaning, the coupling of drug molecules with inactive sites in the body, such that the drug is not accessible for metabolism. This can affect the duration of action of pharmacological agents susceptible to depot binding. One notable example is tetrohydrocannabinol (THC), the main psychoactive component of marijuana. THC is highly lipid soluble, and depot binds in the adipose tissue of users. This drastically slows the metabolism of the drug, which is why metabolites of THC can be detected in urine weeks after the last use. [5][6]

Another factor in drug metabolism is enzyme induction. Enzymes are induced by repeated use of the same chemical. The body becomes accustomed to the constant presence of the drug in question and compensates by increasing the production of the enzyme necessary for the chemical’s metabolism. This is a contributor to pharmacological tolerance and is one reason why patients need ever-increasing doses of certain drugs to produce the same effect. Opioids are a prime example. Patients with long-term prescriptions for opioid analgesics will notice that their medication becomes less effective over time. Notably, induction will increase the metabolic rate for all drugs processed via the enzyme induced; for example, chronic amphetamine use will induce higher concentrations of the enzyme CYP2D6. This enzyme is also important in the metabolism of certain opioids, such as oxycodone; thus, a physician prescribing oxycodone to a patient using amphetamines would have to give the patient a higher dose to produce the desired effect.[7]

In contrast, some drugs have an inhibitory effect on enzymes, making the patient more sensitive to the drugs metabolized with those enzymes. A classic example is the inhibition of monoamine oxidase by certain antidepressant drugs. These compounds produce their psychotherapeutic effects by blocking the enzyme that breaks down ‘pleasure’ chemicals in the brain. However, this can cause problems when patients on an MAOI take drugs that cause abnormally high concentrations of these chemicals. A patient on an MAOI who uses cocaine, which elevates concentration of serotonin, dopamine, and norepinephrine, will experience a much more potent effect from the cocaine. This can lead to numerous physiological problems, including tachycardia, hypertension, and serotonin syndrome.[8]

Drugs which share elements of their metabolic pathways can also ‘compete’ for the same binding sites on enzymes, decreasing the efficiency of their metabolism. For instance, alcohol and certain sedatives are metabolized by the same member of the cytochrome P450 family. Only a limited number of enzymes exist to break these chemicals down. Thus, if a patient were administered pentobarbital whilst also metabolizing alcohol, the pentobarbital would not be completely metabolized because most of the necessary enzymes would be filled by alcohol molecules. This is one reason that alcohol and other sedative/hypnotic drugs can have a synergistic effect when co-administered.