Biotransformations indicate the various chemical modifications which undergo drugs in the body to give metabolites. The biotransformations of drugs are primarily carried out by enzymes, but some of them are done without enzyme intervention, for example hydrolysis in acid or alkaline medium.

Certain drugs in the body do not undergo biotransformation and are eliminated unchanged, but most of them are converted in one or many metabolites, sometimes more than ten.

Each metabolite, m1, m2, m3, formed from the drug D can be more or less active, more or less toxic, can have similar, different, or even antagonist properties compared to those of the drug D. However, generally, the biotransformations are reactions of defence of the body leading to molecules less toxic and less active than the initial molecule, but several exceptions to this rule exist. From a pharmacokinetic point of view, each metabolite of a drug must be regarded as a new molecule having its own features (half-life, volume of distribution, elimination etc) generally different from those of D but able to modify them.

When the product administered is inactive and its metabolite active, it is called a “prodrug”.

Schematically, there are two types of biotransformations classified as phase I and phase II.

Phase I, oxidations

Phase I indicates the biotransformations whose reactional mechanism implies an oxidation which is not always chemically apparent in the end product obtained.

It concerns reactions of hydroxylation (RCH ® RCOH, R which can be aliphatic or aromatic and C a carbon), of N-oxidation (R1-NH-R2 ® R1-NOH-R2), of S-oxidation (R1-S-R2 ® R1-SO-R2) where oxidation is obvious because there is addition of an oxygen atom, and N reactions and O-dealkylation, where the binding of an oxygen atom was only one intermediate step and does not appear in the end product.

A very great number of reactions of oxidation are catalyzed by the P-450 cytochromes. The P-450 cytochromes constitute, in fact, not a single enzyme but a family of iso-enzymes with iron, metabolizing preferentially such or such a type of drug. The changes of the degree of oxydoreduction of iron are at the origin of the biotransformations.

The activity of the P-450 cytochromes, CYP, requires the presence of an enzyme partner, called cytochrome P-450 reductase, which takes two electrons from a reduced flavoprotein to transfer them to the substrate which is oxidized. The flavoprotein itself receives its electrons from NADPH + H+.

There are many Iso-forms of P450 cytochromes, CYP, classified in families named 1, 2, 3, each family is subdivided into sub-groups named by letters A, B etc. Each family metabolizes preferentially certain substrates which, moreover, can be inducers or inhibitors of CYP:

  • CYP 1A2 metabolizes, for example, caffeine, theophylline, clozapine, imipramine, tacrine. It is induced by tobacco.
  • CYP 2C9 metabolizes phenytoine, tolbutamide, ibuprofen, warfarin.
  • CYP 2I9 metabolizes, omeprazole, moclobemide, diazepam, imipramine.
  • CYP 2D6 metabolizes various antidepressants, various neuroleptics, beta-blockers.
  • CYP 3A, in particular CYP3A4 metabolizes clozapine, terfenadine, cisapride, erythromycin, cyclosporine, nifedipine. cortisol, progesterone, testosterone. Ketoconazole and erythromycin are inhibitors of the CYP 3A.
  • CYP 2E1 metabolizes small molecules such as inhalational anesthetics.

The same drug can be metabolized by two or several different iso-enzymes.

One finds in the literature tables indicating the list of drugs preferentially metabolized by the different isoforms of P-450 cytochromes. The monograph of each drug indicates its type of metabolism.

The P-450 cytochromes are also responsible for the transformation of certain procarcinogenes into carcinogenes, in particular by epoxy formation.

There are great differences between the activity of CYP, of genetic origin or acquired by induction or inhibition.

Simplified diagram of the oxidation of a drug by the P-450 cytochromes

Phase II, conjugations

Phase II includes the reactions of conjugation, either by glucuronic acid (glucuronidation), glycine (glycoconjugation), or sulfate (sulfoconjugation catalyzed by sulfotransferases) or acetate (acetylation catalyzed by N-acetyl transferases) and glutathione.

Glucuronidation constitutes the principal mechanism. It is catalyzed by UDP-glucuronyl-transferases which induce the binding of glucuronic acid to an atom of oxygen, nitrogen or sulfur of a molecule. Morphine and acetaminophen are two examples of drugs which are metabolised by glucuronidation.

Glucuronidation of a substrate

Glutathione transferases are the enzymes which induce the binding of a molecule of glutathione which is a tripeptide to an electrophilic atom of another molecule.

Acetylation, under the influence of N-acetyl transferase, relates to a certain number of drugs such as isoniazid which is thus inactivated and hydralazine, sulfapyridine, sulfamethoxazole, dapsone, a metabolite of nitrazepam, procaïnamide and a metabolite of caffeine.

Generally, the conjugation leads to products less active than the initial drug, but there are exceptions illustrated by the example of morphine. Morphine has two OH groups. The metabolite obtained by glycuronoconjugation of OH group in position 6 is an active agonist, whereas the metabolite resulting from the conjugation of OH group in 3 position is an antagonist.

Differences in enzymatic activity  

The activity of certain enzymes implicated in drug biotransformations can be different according to individuals and for the same individual according to whether he takes certain drugs or not.

Differences related to patients

  • Of genetic origin: individuals do not have the same enzymatic equipment and the rate of drug metabolism. For example, the acetylation of isoniazid is rapid in fast acetylators with a half-life of 1 hour and slow in slow acetylators with a half-life of 3 hours. A certain number of tests consisting in the administration drugs like debrisoquine, caffeine or isoniazid and the follow-up of their metabolism were used to appreciate the metabolic characteristics of patients. However, from now on, techniques of direct determination of the genotype will be these methods based on the measure of the concentration of drugs and their metabolites.
  • Of physiological origin: the activity of enzymes can vary during development. In the new-born baby and over more in the premature, biotransformations of drugs can be slower than in adults.
  • Of pathological origin: severe hepatic damage can slow down the elimination of certain drugs by decreasing the activity of the enzymes involved in biotransformations .In addition to this decrease, there are disorders of hepatic circulation and a decrease of hepatic synthesis of plasma proteins involved in drug transport.

Differences induced by drugs

The activity of enzymes can be modified by the intake of drugs. One observes either an inhibition or an induction.

Enzymatic inhibition

Sometimes the enzymatic inhibition is required because it has therapeutic applications for example monoamine-oxidase inhibition or cholinesterase inhibition.

Often it is fortuitous, it occurs with drugs not used for inhibiting enzymes but for other purposes. These drugs inhibit enzymes involved in drug biotransformations such as P450 cytochromes, leading to slowing inactivation of other drugs.

There are many examples:

  • sodium valproate inhibits the hydroxylation of phenobarbital.
  • cimetidine inhibits the hydroxylation of several other drugs such as warfarin .
  • macrolides, like erythromycin and troleandomycine which is not marketed any more, inhibit the catabolism of other drugs like theophylline, carbamazepine and ergot derivatives. The simultaneous use of troleandomycin and ergotamine which has a potent vasoconstrictive effect induced very severe accidents of ischemia, due to the accumulation of ergotamine.
  • antiproteases, in particular ritonavir, inhibit the P450 cytochromes and slow down the biotransformations of various drugs which accumulate in the body..
  • a compound present in grapefruit juice, naringenin and perhaps another compound, inhibit CYP3A4, which slows down the catabolism of certain drugs like cyclosporine and terfenadine, which was withdrawn from the market, calcium antagonists, so that their plasma concentration rises sometimes excessively. An intestinal inhibition of P-glycoprotein could be induced by naringenin; this constitutes an example of modification of the metabolism of drugs by a food product.

The inhibition of the catabolism of a drug by another drug can, under particular conditions, be used in therapeutics, for example to reduce the dosage of an expensive drug.

Enzyme induction

Enzyme induction was demonstrated initially in animals. It was noted that mice or rats which had received a hypnotic dose of phenobarbital a few days before a second administration became insensitive to its hypnotic effect. It was shown that this loss of activity came primarily from a faster inactivation of phenobarbital. The first administration elicited an increased synthesis of enzymes of oxidation, P-450 cytochromes, responsible of the accelerated inactivation of phenobarbital by hydroxylation at the second administration.

Enzyme induction is a non immediate phenomenon, which moreover is reversible, i.e. attenuates and disappears with time.

Induction is generally rather specific, but its consequences can concern several molecules because the enzymes whose synthesis is increased can metabolize other molecules than the inducer itself. The inducer can thus be at the origin of pharmacokinetic drug interactions.

The main inducing drugs are barbiturates (phenobarbital), equanil or procalmadiol, carbamazepine, rifampin. A drug of vegetable origin, St. John's wort or Hypericum perforatum having an antidepressant activity, is also an enzymatic inducer likely to lower the plasma concentration of drugs such as cyclosporine.

Enzyme induction can have two kinds of consequences:

  1. In pharmacology: the loss or decrease of efficacy of the inductive drug itself and of other drugs which are inactivated by the same enzymatic reactions. Thus the intake of an enzyme-inducing drug such as as rifampin can make cortisol ineffective, for example, and induce the reappearance of asthmatic attacks or make an oral contraceptive ineffective leading to an undesired pregnancy.
    Tobacco modifies the metabolism of many drugs; it accelerates the inactivation of theophylline and propanolol.
  2. In pathology: in patients with latent or known deficiencies of certain steps of heme synthesis, the increase of activity of acid aminolevulinic synthase (enzyme which catalyzes an initial step of the synthesis of heme), after the intake of an enzyme-inducing drug, causes an accumulation of porphyrins and attacks of porphyria.

Induction of P-450 cytochromes implicated in the biotransformations of drugs results from an increase in the transcription of genes (DNA) in mRNA coding for the cytochromes. A stabilization of the mRNA can also increase its translation. Drugs or xenobiotics increase the transcription in the same way as hormones with nuclear effect (see transduction) via transcriptional factors which interact with DNA. One of these factors is PPAR (peroxisome proliferator-activated receptor).

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Quizz : Q 171
An patient is treated continuously with a D1drug metabolized by the cytochrome P450 3A4. The plasma concentration of D1 is stable. For an intercurrent trouble he receives another drug D2 which is an enzymatic inducer of the CYP3A4. This second drug is highly likely to elicit:
a lengthening of the plasma half-life of D1
a decrease of the plasma concentration of D1
a reduction of the volume of distribution of D1
an increase in the bioavailability of D1
redistribution of D1 in a second compartment

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165 The enzymatic inducing effect of a drug,...

  Last update : August 19, 2006  
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