Metabolism of the Medicines

Metabolism is the biotransformation of a drug within the body into other molecular species known as metabolites.  While we usually think of metabolism of a drug as a de-activation of it, some cancer drugs actually require some metabolic change inside the body before they become active against malignant cells.

The liver is the primary site of metabolism for many drugs, the cells involved being those of the smooth endoplasmic reticulum.  One way in which the liver processes drugs is acetylation, the addition of an acetyl group to the molecule. Some people are fast acetylators and some people are slow acetylators. This is determined genetically. Slow acetylators may suffer medicine side effects more because more of the drug reaches their bloodstream. Fast acetylators may process drugs too rapidly for them to benefit from the drug’s intended therapeutic effects.

There are two main phases of metabolism. In Phase I the drug undergoes catabolic reactions such as hydrolysis, reduction, oxidation, and condensation. Some of the resulting substances (metabolites) can be pharmacologically active in themselves. Indeed, one strategy in drug delivery is to give the patient a biologically inactive “pro-drug” which the body breaks down into an active form during this phase. Enzymes involved in Phase I are mainly the cytochrome P450 family of enzymes, which are mainly contained in the liver.

In Phase II the drug undergoes a conjugation reaction that forms a covalent linkage with an endogenous substance such as glucuronic acid, phosphoadenosyl phosphosulfate, glutathione, amino acids, acetyl-CoA or S-adenosyl-methionine. These reactions involve the polar functional groups of products of Phase 1 metabolism. The resulting substances from the Phase II reactions are for the most part pharmacologically inactive. Biotransformation of drugs to hydrophilic molecules results in their being more easily excreted from the body. Drug metabolism is affected by age, sex, genetics, intestinal flora, enterohepatic circulation and nutritional status.

Excretion of the Medicines

Excretion occurs mainly either via the kidneys or the bile. Kidney health and capacity is important for renally excreted drugs. This is termed clearance, which is a measurement of renal excretion ability and is important in estimating correct long-term drug dosing. Measurements of clearance are per unit time.

The processes of renal clearance include secretion, filtration by the glomerulus and passive reabsorption of the drug back into the blood. Passage through the liver makes metabolites more polar and therefore more water soluble; the resulting metabolites are then more easily excreted via the kidney system.

Clearance, CL, can be calculated by multiplying the elimination constant, k_el by the volume of distribution, V_d , thus:

CL_t = k_el x V_d

Creatinine is a substance that is filtered by the kidney but not reabsorbed, and can therefore be used to estimate glomerular filtration  rate. It will parallel any changes in secretion and reabsorption.

Creatinine clearance is abbreviated as CL_cr where CL = rate of elimination.

Creatinine clearance in a new patient can be deduced by using the known CL_cr / K_el relationship to estimate the elimination rate constant. This enables the physician to calculate a suitable dosage of a drug for that patient.

The half life of a drug is the time it takes for the amount of drug to reduce by one half during elimination. Most drugs are prescribed to be taken or administered at fixed intervals over a period of time. If the drug has a short half life, the dosing interval needs to be more frequent in order to achieve the therapeutic objective.

Urinary pH affects drug reabsorption and excretion.  Ph of urine can vary from 4.5 to 8.

Related: Drug-Drug Interactions