To simplify, we will focus only on hepatic medicine metabolism in relation with genetic polymorphisms and we will discuss the transportation mechanisms through membranes and the action of receptor-binding in the target organ. Although, conceptually, the result is same; more activity or less activity, i.e. more drug absorption through a membrane, or more drug delivery from the inside of a cell to the outside; more receptor-binding has a better therapeutic effect, less receptor-binding lessens therapeutic effect. This process takes place when a drug that bonds through a “key-lock effect” to a specific protein.

The structure of an enzyme – of a protein in general therms – is defined by a gene. There are 25,000 typified genes in our own organism alone. It is known that no more than 30 genes intervene in the hepatic metabolism of medicine. Genes have polymorphisms and these can affect (or not) the activity of the enzymes they encode. Many polymorphisms are being detected in most genes but, fortunately, most of them do not cause any functional changes in the encoded protein, so there is no interest in their study in clinical practice. In the case of modification, these polymorphisms become part of the set to be studied in pharmacogenetic applications. Considering their incidence in the population, these are not taken into account when their incidence is less than 2-3% of the population This varies according to ethnicity.

We need to bear in mind that we have two copies of each gene called the alleles; one coming from paternal inheritance and the other one from maternal inheritance. People who have a gene with two alleles of ancestral structure belong to the majority group of population. It is considered to be the “normal” case as shown in most clinical trials. This group is categorized as “wild type” (wt) and patients tend to metabolize drugs as intended, thus,  international nomenclature define them as EM phenotype or Extensive Metabolizers.

However, a significant part of the population may have a mutated allele, which causes a change in the enzyme structure and so in its activity. These people will have only one active allele, so they will produce half of the structurally functional enzyme, half of its activity and, therefore, they will need half of the drug dose to experience the same effect -there are many works that define this concept more individually. In this case, we will define them as IM phenotype people or Intermediate Metabolizers.

Two non-functional alleles -equal or different- can be inherited and, then, there will be virtually no functional enzyme synthesis -there are residual activities ranging from 1 to 10%. In these cases, some drugs should not be prescribed because due to a high overdose risk. A drug with similar pharmacological action should be recommended instead, which will be metabolized by another enzyme in which the patient has no abnormal polymorphism. This case is defined as PM phenotype or Poor Metabolizers.

There may also be EM phenotype patients who have gene duplication -or more replicates of the gene-, so much more of the enzyme will be produced -there are several “production chains”. Therefore, drugs will be metabolized very quickly. This case is defined as UM phenotype  or Ultra rapid Metabolizer. These kind of patients will experience a therapeutic failure, so drugs with the same therapetic effect and not metabolized by this enzyme are required.

The goal for therapeutic success is to keep blood levels within a range called the “therapeutic window“. Plasma concentrations within this range produce the desired therapeutic action. Below  this level, therapeutic failure occurs, and above it pacients may face adverse effects due to overdose. Drug absorption process reaches a maximum level according to the dose – generally at 2-3 hours – and goes down. When subtherapeutic concentration is reached, another dose must be administered. This functioning explains why a dose should be given every 6, every 8, every 12 or 24 hours, according to the dosage recommended in the brochure. The plasma concentrations’ graph as a function of time is what is known as drug pharmacokinetics.

If the dose calculated for the EM phenotype group is administered to an IM patient, higher drug levels in blood will be reached, since the rate of elimination will be lower. In these cases it is advisable to decrease the dose between 30-50% although, sometimes, if the therapeutic window is wide, satisfactory results can be obtained even if in a state of a slight overdose. This has to be specified for each drug.

But if the patient is a PM phenotype drug will practically go uneliminated. Every extra dose will add a on the not yet eliminated previous dose has not yet been eliminated. Such additive process every 6, 8 or 12 hours, and after one week, ends up in an overdose and the adverse effects start to appear. On the other hand, if the patient is a UM phenotype, the drug will be eliminated very quickly and within the inter dose intervals the patient will be on a subtherapeutic level.

Therefore, through a study of genetic polymorphisms -patients’ phenotype- a personalized dose protocol can be known in advance.