What is the process called when an active drug turns into an inactive metabolite?

Metabolism is the biotransformation that some drugs undergo when the body chemically alters them. Metabolism is an important process that produces the intended therapeutic effects of a certain drug and eliminates the drug from the body through urine or bile. Drug metabolism can be tricky to understand—here’s everything you need to know about how drugs are metabolized in the body. 

Active and Inactive Substances 

The substances that result from metabolism, known as metabolites, may be inactive. They may be similar to or different from the original drug in therapeutic activity or toxicity. Some drugs, called prodrugs, are administered in an inactive form and then metabolized into an active form. The resulting active metabolites produce the desired therapeutic effects.  

Other metabolites may be metabolized further instead of being excreted from the body. The subsequent metabolites are then excreted from the body.  

The Primary Site of Metabolism 

Most drugs must pass through the liver, which is the primary site of drug metabolism. Once in the liver, enzymes convert prodrugs into active metabolites or convert active drugs into inactive forms. The liver’s primary mechanism for metabolizing drugs is a specific group of cytochrome P-450 enzymes. This group of enzymes acts as a catalyst for the oxidation of many drugs. The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized. However, the capacity of the enzymes to metabolize is limited, so they can become overloaded when blood levels of a drug are high. 

Reactions for Metabolism 

Drugs are metabolized in several ways, including the following reactions: 

• Oxidation 
• Reduction 
• Hydrolysis 
• Hydration 
• Conjugation 
• Condensation 
• Isomerization 

Patient Variability 

The rate of drug metabolism can vary depending on the patient. The patient’s metabolism rate, which may be very high or very low, specifically affects the efficacy and toxicity of the drug. For example, rapid metabolizers can clear the drug very quickly, so the full therapeutic concentration of the drug in the blood and tissues may not be fully reached. In patients with slower metabolisms, the drug is metabolized so slowly that it accumulates in the bloodstream. For these patients, the higher concentration of the drug in the body creates a greater potential for adverse effects. 

A few specific patient factors can affect how quickly or slowly a drug is metabolized, including genetic predisposition, chronic liver disorders, advanced heart failure, and interactions with concurrent medications.  

The Two Phases of Metabolism  

There are two phases of drug metabolism, known as Phase I and Phase II. Phase I reactions involve the formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis). These reactions are non-synthetic. Phase II reactions involve conjugation with an endogenous substance (e.g., glucuronic acid, sulfate, glycine). These reactions are synthetic. 

Metabolites that are formed in Phase II through synthetic reactions are typically easier to excrete because they’re more polar than Phase I metabolites. It’s important to note that the phases, contrary to what their names suggest, refer to the type of reaction at hand, not the order in which they occur.  

Metabolism Rates 

Most drugs have an upper limit for the rate of metabolism. This limit is due to the saturation of the enzymes needed in order for the metabolic pathway to take place. However, the therapeutic doses usually used are significantly below the level of saturation. As a result, the metabolism rate increases with the concentration of the drug. This process is referred to as first-order kinetics. In first-order kinetics, the metabolism rate is a constant fraction of the concentration of the drug in the body. 

In some cases, therapeutic doses of the drug can lead to the saturation of the enzyme sites. When this happens, the metabolism remains constant despite the doses of the drug being increased. This is referred to as zero-order kinetics. 

Metabolic Enzymes 

As we previously mentioned, the most common and important enzyme group is the cytochrome P-450 (CYP450) group. This enzyme group is specifically involved in Phase I metabolism of drugs. Some of the important enzymes in this family include: 

• CYP1A2 
• CYP2C9 
• CYP2C19 
• CYP2D6 
• CYP2E1 
• CYP3A4 

Other concurrent drugs and substances in foods or herbal remedies can affect these enzymes as well, which in turn can change the rate of the metabolism of drugs. If these substances decrease the ability of the enzymes to break down a drug, then that drug’s effects—including its side effects—are increased. If the substances increase the ability of the enzymes to break down a drug, then that drug’s effects are decreased. 

Aging also alters the effects of metabolic enzymes. With aging, the capacity of the CYP450 metabolism decreases by at least 30%, most likely due to changes in hepatic volume and blood flow. Due to this, the dosage of drugs often needs to be reduced in elderly patients. 

Conjugation 

Glucuronidation is the most common type of Phase II reaction, occurring in the microsomal enzyme system of the liver. This reaction increases the solubility of the drugs so that they can be secreted in the bile or urine. Aging does not affect the metabolic rate of glucuronidation, and there’s therefore not usually a need to reduce the dose of such drugs for metabolic reasons in the elderly—unlike the repercussions of the cytochrome P-450 group of enzymes in Phase I. 

Pharmaceutical Manufacturing Companies and Drug Metabolism  

Pharmacokinetics refers to what the body does to a drug and includes multiple factors of a drug’s properties, including the movement of the drug into, through, and out of the body and the time course of its absorption, bioavailability, distribution, metabolism, and excretion. Drug pharmacokinetics also determine the onset, duration, and intensity of a drug’s effect, which often largely depend on patient-related factors as well as the drug’s chemical properties. 

Because metabolism plays a role in pharmacokinetics, the drug discovery and development performed by pharmaceutical manufacturing companiesis highly crucial to understanding how a drug metabolizes in the body based on patient factors and the chemical properties used in the drug.