The biochemical basis of important drug interactions

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Introduction

The biotransformation of a drug may either lead to the termination of its pharmacological activity or, occasionally, to its activation to a pharmacologically effective entity. It is also possible that a drug may be metabolized to form pharmacologically or toxicologically active metabolites. Whatever the outcome, the biotransformation of a drug ultimately involves its conversion to a more hydrophilic form thereby facilitating its excretion into the urine. However, some lipophilic drugs and their metabolites are excreted via the bile into the intestine while others, that are volatile, pass into the lungs and are thereby excreted in the expired air.

The biotransformation of drugs occurs in two main phases which are summarized in Table 3.2. Phase 1 involves the oxidative catabolism of the drug. The end products of the phase 1 reactions are generally conjugated by uridine diphosphorylglucuronyl transferase, sulphatase or N-acetyltrans-ferase to form polar, water-soluble products which are then excreted into the urine. These are the products of the phase 2 reactions. While it is well known that products of the phase 1 reactions are often pharmacologically active (for example, norfluoxetine which is a metabolic product of fluoxetine), it is also possible that the end product of phase 2 reactions can also be pharmacologically active. For example, morphine-6-glucuronide is as pharmacologically active as the parent compound.

These stages can be illustrated schematically as shown in Figure 3.1. The primary site of biotransformation is the liver although the gastrointestinal tract, kidneys and the skin also contribute to a minor extent.

Drugs that are orally administered often undergo first-pass metabolism. This involves their (generally partial) metabolism in the liver following their entry from the gastrointestinal tract via the portal circulation. This

Table 3.2. Biotransformation of drugs by phase 1 and phase 2 reactions

Phase 1 reactions Oxidative reactions involving n- and o-dealkylation, aliphatic and aromatic hydroxylation, n- and s-oxidation, deamination. Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation.

R> >>>>>>>>>>>>> I Phase 1 oxidation

R-O >>>>>>>>>>>>>> "R-O-Y Phase 2 conjugation

Reactive metabolites (usually minor)

Elimination as inactive (usually by the kidneys)

[Y]=glucuronide, sulphate or acetyl group. Figure 3.1. Relationship between the phase 1 and 2 biotransformation reactions.

inevitably leads to a reduction in the effective blood concentration and must therefore be taken into account when the dose of the drug to be administered is calculated.

In the liver, the microsomal enzymes that are responsible for catalysing the oxidative reactions are the cytochrome P450 family of enzymes. These enzymes are haem-containing membrane proteins that are bound to the smooth endoplasmic reticulum of the hepatocytes. Of the 12 gene families of the cytochrome P450 system that have been identified in man, those classified as cytochrome P450 types 1, 2 and 3 account for most of the drug biotransformations. In addition to the oxidative reactions undertaken by the P450 enzymes (also known as isozymes), hydrolytic reactions are carried out by epoxide hydrolase and several amidases, esterases, proteases and peptidases.

There are several important factors which may influence biotransformation reactions. Thus some drugs or toxins may induce the synthesis of microsomal oxidases by the liver (for example, a barbiturate) and thereby enhance the metabolism of the drug, or any other drug given concurrently which is metabolized by the same enzyme system (for example, warfarin). Nicotine in tobacco smoke is known to increase the activity of the cytochrome P450 1A2 isozyme which may predispose some individuals to a greater risk of cancer. Some drugs produce hepatotoxic metabolites which thereby impair the biotransformation of other drugs or toxins which may be present. For example, chronic alcohol intake can lead to the formation of hepatotoxic metabolites. Drugs may also selectively inhibit individual isozymes of the P450 system, thereby causing an unexpected rise in the blood and tissue concentrations of any drug given concurrently which is also metabolized by that isozyme. The SSRI antidepressants for example have been shown to act as inhibitors of some P450 isozymes, thereby not only reducing their own metabolism but also those of other drugs given concurrently (see p. 89). Some foods may also inhibit the P450 isozymes and thereby enhance the toxicity, or the duration and magnitude of the therapeutic response of a drug given concurrently. Grapefruit juice, for example, is a significant inhibitor of the P450 isozyme 3A4, an enzyme which is widely involved in the metabolism of psychotropic drugs (see p. 89).

It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes.

Classification of the cytochrome P450 enzymes

These enzymes have been classified according to the degree of structural similarity in their amino acid structures (the so-called sequence homology). Thus the closer the enzymes are from both the phylogenic and functional point of view, the more likely they are to be a member of the same enzyme family with a sequence homology of at least 40%. The enzymes are further grouped into subfamilies (isozymes) which are designated by the letters A, B, C, D, E, F. All enzymes in the same subfamily have a sequence homology of at least 55%. The final number designates the gene that codes for a specific enzyme (1, 2, 3,4, 5, 6, 7, etc.). With regard to the metabolism of the psychotropic drugs, cytokines 1A2, 2C19, 2D6, 3A3/4 are of primary importance.

The cytochrome P450 enzymes are divided into two major groups, namely the ''steroidogenic'' enzymes (which are the phylogenically older type and are responsible for the synthesis of steroids and related compounds comprising the cell wall) and the ''xenobiotic'' type (located in the smooth endoplasmic reticulum and involved in the metabolism of foreign, or xenobiotic, compounds which include all drugs). The following list summarizes the types of compounds metabolized by the main groups of P450 enzymes:

• Steroidogenic type - steroids, bile acids, cholesterol, prostaglandin biosynthesis.

• Xenobiotic type - drugs, toxins, carcinogens, mutagens.

It should be noted that the genetic information for the P450 enzymes is present throughout in all tissues, but knowledge of the role of the enzymes in tissues other than the liver and gastrointestinal tract is unclear. For example, cytochrome P450 2D6 is found in the brain where it is linked to the dopamine transporter. Whether a deficit in the activity of this enzyme is responsible for predisposing some individuals to Parkinson's disease is a matter of conjecture.

Table 3.3. Main types of drug metabolized by cytochrome P450 isozymes

Antidepressants - tricyclics, mirtazepine, fluoxetine* Antipsychotics - clozapine, haloperidol, olanzapine, phenothiazines Sedative/hypnotics - zopiclone Beta-blockers - propranolol, warfarin, theophylline

Antidepressants - amitriptyline, clomipramine, imipramine, moclobemide, citalopram Antipsychotics - olanzapine

Mood stabilizers - phenytoin, valproate, topiramate Sedative/anxiolytics - diazepam, barbiturates Beta-blockers - propranolol

Antidepressants - tricyclics, fluoxetine*, paroxetine*, sertraline*, mirtazepine, venlafaxine, mianserin Antipsychotics - phenothiazines, haloperidol, clozapine, olanzapine, quetiapine Antiarrhythmics - encainide, flecainide, mexiletine Beta-blockers - alprenolol, metoprolol, propranolol, timolol Opiates - codeine, dextromethorphan, ethylmorphine

Antidepressants - tricyclics, nefazodone*, fluoxetine*, fluvoxamine*, citalopram, mirtazepine, venlafaxine Antipsychotics - chlorpromazine, clozapine, pimozide, quetiapine, risperidone Anxiolytics - clonazepam, diazepam, temazepam, triazolam, alprazolam, midazolam, buspirone Anticonvulsants - ethosuximide, carbamazepine Calcium channel blockers - diltiazem, felodipine, nifedipine, verapamil

Antibiotics - clarithromycin, erythromycin Others - omeprazole, cisapride, dapsone, lavastatin

*Also inhibits this enzyme.

A summary of the main classes of psychotropic drugs metabolized by the P450 enzymes, together with some of the drugs of other classes with which they may interact, is given in Table 3.3.

Drug-drug interactions

There are two main types of drug interactions, pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions arise when one drug increases or decreases the pharmacological effect caused by a second drug that may be given concurrently. Pharmacokinetic interactions occur when one drug alters a pharmacokinetic component of another drug thereby causing a change in its effective concentration at its site of action. The relationship between the pharmacodynamic and pharmacokinetic

CypP450 1A2

CypP450 2C19

CypP450 2D6

CypP450 3A3/4

characteristics and the subsequent therapeutic response can be summarized by the following equations:

Magnitude of therapeutic response = drug pharmacodynamics + drug pharmacokinetics + individual biological variation

Magnitude of clinical response = potency at site of action + drug concentration at site of action + biological status of the patient

With regard to the differences between the pharmacodynamic and pharmacokinetic drug interactions, it would appear that pharmaco-kinetic interaction produces the same result as a change in the dose of the drug. For example, combining the SSRI antidepressant fluoxetine with a sub-therapeutic dose of a tricyclic antidepressant could result in a two- to threefold elevation in the blood concentration of the tricyclic as fluoxetine inhibits its metabolism via the 2D6/3A4 isozymes. However this change in the pharmacodynamic response to the tricyclic antidepressant could (a) result in unexpected cardiotoxicity due to the abrupt increase in the concentration of the drug in the cardiac tissue resulting in the block of the fast sodium channels and (b) prolong the elimination half-life of the tricyclic antidepressant thereby resulting in a cumulative toxicity of the drug. Thus the SSRI, by inhibiting the metabolism of the tricyclic, has changed the clearance of the drug as illustrated by the equation:

Rate of dosing/Clearance!Steady-state concentration!Therapeutic response

By decreasing the clearance due to cytochrome P450 inhibition, but maintaining the same dose and rate of dosing, the steady-state concentration of the tricyclic antidepressant increases thereby enhancing the therapeutic or toxicological response. In clinical practice, pharmacokinetic drug interactions may be dismissed as an idiosyncrasy of the patient rather than a potential drug hazard.

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure.

In addition to the above examples, toxicity problems can also arise when one drug induces the metabolism of the second drug. Toxic metabolites, which are not normally present in a sufficiently high concentration to be noticeable, may increase due to the increase in their concentration as a consequence of enzyme induction. For example, carbamazepine induces P450 3A3/4 which enhances the metabolism of valproate. This leads to the increased production of the 4-ene metabolite of valproate which is hepatotoxic.

Hopefully these few examples will serve to emphasize the importance of a knowledge of the pharmacokinetic features of psychotropic drugs in order to avoid the potentially serious side effects that can result from drug interactions.

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