Question

Many adverse drug reactions occur because of the activity of drugs as inducers and/or inhibitors of key metabolic enzymes such as the cytochrome P450 family. Explain how a drug can be an enzyme inducer and how it is possible for a drug to be both an enzyme inhibitor and an enzyme inducer.

Answer 1

          Adverse Drug Reactions

                                              Adverse reaction. WHO, (1972) 'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function'.

                      An adverse drug reaction (ADR) is an injury caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. Many adverse drug reactions occur because of the activity of drugs as inducers and/or inhibitors of key metabolic enzymes such as the cytochrome P450 family.

             Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. Cytochrome P450 enzymes play a role in the synthesis of many molecules including steroid hormones, certain fats (cholesterol and other fatty acids), and acids used to digest fats (bile acids).

There are several terms commonly used to describe adverse effects of drug therapy:

• An adverse drug reaction (ADR) is an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug. An ADR will usually require the drug to be discontinued or the dose reduced.
• An adverse event is harm that occurs while a patient is taking a drug, irrespective of whether the drug is suspected to be the cause.
• A side-effect is any effect caused by a drug other than the intended therapeutic effect, whether beneficial, neutral or harmful. The term ‘side-effect’ is often used interchangeably with ‘ADR’ although the former usually implies an effect that is less harmful, predictable and may not even require discontinuation of therapy (e.g. ankle oedema with vasodilators).
• Drug toxicity describes adverse effects of a drug that occur because the dose or plasma concentration has risen above the therapeutic range, either unintentionally or intentionally (drug overdose).
• Drug abuse is the misuse of recreational or therapeutic drugs that may lead to addiction or dependence, serious physiological injury (such as damage to kidneys, liver, heart), psychological harm (abnormal behaviour patterns, hallucinations, memory loss), or death.

A drug can be an enzyme inducer

                 

                An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme.

                     Enzyme induction refers to an increase in the rate of hepatic metabolism, mediated by increased transcription of mRNA encoding the genes for drug-metabolizing enzymes. This leads to a decrease in the concentrations of drugs metabolized by the same enzyme.

                        One important source of interaction stems from a family of enzymes that is important for the body's ability to metabolize or “get rid of” certain drugs. The Cytochrome p450 oxygenases or p450 enzyme system is responsible for metabolizing many drugs and removing or neutralizing toxins in our body.

                                    

                          The properties of the hepatic microsomal, drug detoxicating, enzyme system is reviewed with particular reference to its inducibility. Induction is modified by various factors of which the diet is particularly important. A theoretical model system for induction has been proposed and this is discussed. There are a number of methods for assessing microsomal enzyme induction in man, none of which is ideal. Nevertheless, induction is a well-recognised phenomenon in man and has a bearing on the metabolism of a number of endogenous substances. The effect of induction on steroid metabolism and the relationship between inducers, vitamin D, and metabolic bone disease is discussed. Bilirubin metabolism is affected by changes in microsomal enzyme activity and inducers have been used therapeutically in some cases of hyperbilirubinemia. The relationship between drugs and the hepatic porphyrias is reviewed. The hepatic microsomal enzyme system is but one of many inducible enzymes and the role of induction in general in metabolic regulation is emphasised.

              
              Bosentan is a substrate of cytochrome P450 (CYP) 3A4 and CYP2C9. It is also known to be an inducer of CYP3A4 and CYP2C9 and may induce other isoenzymes as well. Thus, it would be expected to induce its own metabolism with chronic dosing, and steady-state plasma concentrations have been noted to be reduced to 50% to 60% of single-dose levels.

                 Amiodarone is a substrate of CYP3A4 and CYP2C8 and an inhibitor of CYP2C9, CYP2D6, CYP3A4, and p-glycoprotein. Based on these assumptions, there are several potential interactions that could occur when amiodarone and bosentan are administered:

1) Bosentan could induce amiodarone metabolism via CYP3A4. This could lead to reduced antiarrhythmic efficacy of amiodarone.

2) Amiodarone could inhibit bosentan metabolism via CYP3A4 and/or CYP2C9. Increased bosentan response or side effects may occur. This raises the question of what outcome might be expected when the induction of CYP3A4 (via bosentan) is combined with the inhibition of CYP3A4 (via amiodarone).

                

                  Enzyme induction in humans may lead to drug-drug interactions. Possible pharmacokinetic consequences of enzyme induction include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance, or accelerated formation of active or toxic metabolites. The “gold standard” accepted for in vitro enzyme induction assays are freshly isolated human hepatocytes. A procedure for in vitro induction studies in freshly isolated human hepatocytes is described including evaluation of CYP1A2, CYP2B6, and CYP3A4 enzyme activities and mRNA levels, and an example is given.

                     Similarly, since the barbiturates are all metabolized by similar processes, drugs that would be expect to inhibit or induce the metabolism of phenobarbital should inhibit or induce the metabolism of other barbiturates. Examples of both of these mechanisms follow.

Beta-adrenoceptor antagonists

Pentobarbital increases the clearances and reduces the plasma concentrations of some beta-blockers, such as alprenolol ,with loss of beta-blockade. In six healthy subjects pentobarbital 100 mg reduced the plasma concentrations of steady-state oral alprenolol 200 mg/day for 10 days and its metabolite 4-hydroxyalprenolol, without changes in half-lives .

In eight healthy subjects pentobarbital 100 mg/day for 10 days reduced the AUC of metoprolol 100 mg by 32%, with considerable interindividual variability (2–46% ).

Caffeine

In 42 patient’s caffeine 25 mg reduced sleep, pentobarbital 100 mg enhanced it, and in combination the effect was the same as that of placebo.

Cannabinoids

Tetrahydrocannabinol inhibits the metabolism of hexabarbital .

Carbonic anhydrase inhibitors

For the interaction of carbonic anhydrase inhibitors with amobarbital, see above under Nervous system.

Coumarin anticoagulants

They have been several reports of interactions in which barbiturates induce the metabolism of coumarin anticoagulants. These include interactions of:

amobarbital with ethylbiscoumacetate and warfarin

aprobarbital with dicoumarol

butabarbital with phenprocoumon and warfarin

heptabarbital with acenocoumarol biscoumacetate dicoumarol , and warfarin

pentobarbital with acenocoumarol and ethylbiscoumacetate

secobarbital with warfarin

vinbarbital with dicoumarol

Imipramine

A possible interaction of imipramine with butalbital was reported in a 44-year-old woman, in whom depressive symptoms had worsened, despite previously effective treatment with imipramine associated with blood concentrations in the usual target range; butalbital had recently been added and blood imipramine concentrations had fallen by about 50%, which was attributed to induction of CYP1A2.

Metronidazol

Metronidazole inhibits the metabolism of butobarbitone .

Phenazone

Pentobarbital increased the clearance of phenazone by 60% and also increased the clearance of its main metabolites, 4-hydroxyphenazone, norphenazone, and 3-hydroxymethylphenazone + 3-carboxyphenazone, the largest effect being on norphenazone .

Quinidine

The metabolism of quinidine is enhanced by barbiturates, though enzyme induction . This leads to an increase in the first-pass metabolism of quinidine, and thus increased requirements of oral quinidine. In one case, when pentobarbital was withdrawn quinidine metabolism was reduced and the increased quinidine load altered the pharmacokinetics of digoxin (see under Cardiac glycosides), causing digitalis toxicity . Conversely, in another case quinidine inhibited the metabolism of pentobarbital .

Rifamycins

Rifampicin induces the metabolism of hexobarbital

Theophylline

Increases in theophylline clearance have been reported during co-administration of pentobarbital and secobarbital .

Induction and Inhibition of Metabolism

               Metabolism of drugs can be substantially affected by enzyme induction or inhibition by other drugs or chemicals (Box 2.3). In some cases the drug itself may alter its own metabolic fate by induction or inhibition. Many drugs are capable of inducing enzyme activity, thereby increasing the rate of metabolism and hepatic clearance of concurrently administered drugs, which typically results in a decreased pharmacologic effect. Enzyme induction usually occurs slowly, requiring several weeks to reach maximum effect. Induction is accompanied by increased hepatic ribonucleic acid (RNA) and protein synthesis and increased hepatic weight. Enzyme induction is important in the pathogenesis of hepatotoxicity and therapeutic failure of many drugs. Phenobarbital is a potent enzyme inducer known for hepatotoxicity and for inducing its own metabolism. Rifampin induces the metabolism of azole antifungals; concurrent administration with itraconazole results in subtherapeutic itraconazole concentrations

               Drug-induced enzyme inhibition also occurs and typically results in prolonged clearance of a concurrently administered drug. The potential for toxicity or an exaggerated pharmacologic response is increased. In contrast to induction, inhibition occurs rapidly. Erythromycin and enrofloxacin are known inhibitors of the metabolism of theophylline; concurrent administration can cause central nervous system toxicity and seizures.

              Induction of biotransformation enzymes

The total quantity of biotransformation enzymes can be increased in humans and in higher animals by prior administration of chemical inducers, such as anesthetics (nitrous oxide, ether, and chloroform), sedatives (barbiturates and urethane), analgesics (glutethimide and phenylbutazone), and hypoglycemic agents or insecticides (chlordane, DDT, dieldrin, aldrin, hexachlorocyclohexane, and heptachlor).

         Enzyme induction usually requires repeated exposure of the inducing agents, and the effect is usually temporary, lasting from 2 to 4 weeks following the administration of the inducing chemical. Induction of cytochrome P450s can increase the rate of biotransformation and lower the plasma exposure of therapeutic drugs, sometimes leading to ineffective treatment of therapeutic medicines.

                However, enzyme induction is usually less important than inhibition of cytochrome P450s, because some of the aforementioned examples indicate that enzyme inhibition can cause rapidly elevated drug level in the blood, leading to exaggerated toxicity. Nonetheless, induction of biotransformation enzymes can affect metabolism and toxicity of a variety of compounds. For example, CYP2E1 is one of the principal cytochrome P450s responsible for metabolizing acetaminophen. Alcohol is a known CYP2E1 inducer. Chronic alcohol users may have increased levels of the CYP2E1 enzyme that may metabolize more acetaminophen to the toxic metabolite, N-acetybenzoquinoneimine. The excessive amount of N-acetybenzoquinoneimine might deplete glutathione detoxification pathway, leading to liver damage.

                

                  The foregoing discussion on the complexity of biotransformation suggests at least two important mechanisms by which chemically induced toxicity or drug efficacy can be altered. First, the toxicity of a given compound can be distinctly different within members of a species or between species. This suggests that toxicity test should always be performed in more than one species. Second, inhibition or induction of biotransformation enzymes plays a significant role in altering drug-induced toxicities and drug–drug interaction. Besides being substrates for metabolic enzymes, many medicines can also induce or inhibit metabolic enzymes. Precautions must be taken to control for coexposures that might alter efficacy or toxicity of a given compound.

                     Enzyme Inhibition

Mechanisms of Drug Actions by Enzyme Inhibition: a) Direct Enzyme Inhibition: Although activation of enzymes may be exploited therapeutically, most effects are produced by enzyme inhibition. Inhibition caused by drugs may be either reversible or irreversible. A reversible situation occurs when an equilibrium can be established between the enzyme and the inhibitory drug. A competitive inhibition occurs when the drug, as "mimic" of the normal substrate competes with the normal substrate for the active site on the enzyme. Concentration effects are important for competitive inhibition. In noncompetitive inhibition, the drug combines with an enzyme, at a different site other than the active site. The normal substrate cannot displace the drug from this site and cannot interact with the active either since the shape of the enzyme has been altered. Among the many types of drugs that act as enzyme inhibitors the following may be included: antibiotics, acetylchlolinesterase agents, certain antidepressants such as monoamine oxidase inhibitors and some diuretics. b) Suppression of Gene Function: Many drugs act as suppressors of gene function including antibiotics, fungicides, antimalarials and antivirals. Gene function may be suppressed in several steps of protein synthesis or inhibition of nucleic acid biosynthesis. Many substances which inhibit nucleic acid biosynthesis are very toxic since the drug is not very selective in its action between the parasite and host.

c) Antimetabolites:

The strategy of chemotherapy consists of exploiting the biochemical differences between the host and parasite cells. Metabolites are any substances used or produced by biochemical reactions. A drug which possesses a remarkably close chemical similarity (mimic) to the normal metabolite is called an antimetabolite.

The antimetabolite enters a normal synthetic reaction by "fooling" an enzyme and producing a counterfeit metabolite. The counterfeit metabolite inhibits another enzyme or is an unusable fraudulent end product which cannot be utilized by the cell for growth or reproduction. Such antimetabolites have been used as antibacterial or anticancer agents.

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Summary

         It would appear that when potent enzyme inhibitors are combined with potent inducers, the inhibition will tend to predominate. Unlike inhibitors where the inhibitory activity often abates when the drug is discontinued, recovery from induction may take several days following the withdrawal of the inducer.

Upon discontinuation of the drugs, be alert for a rapid shift to induction and potential reduction in object drug effect. As always, patient monitoring with appropriate drug dose adjustment is extremely important with these complex interactions.

Conclusion

             The first-pass metabolism of a drug that mainly takes place in the gastrointestinal tract (GIT) and liver greatly reduces the systemic bioavailability as well as the efficacy of an orally administered drug as compared to the parenteral drugs. Thus, it is very essential to understand and consider the various physicochemical and physiological factors like molecular properties of drug, enzyme induction and inhibition, disease state, age, gender, genetic polymorphism etc. affecting the first-pass metabolism of a drug. Such considerations during the process of drug development are of prime importance to design an appropriate formulation with proper excipients in order to enhance the bioavailability while maintaining the efficacy of drugs. The role of various physiological and biochemical factors affecting the first-pass metabolism of a drug in GIT and liver such as of gastrointestinal motility, hepatic blood supply, plasma protein binding, genetic polymorphism, dose, and route of administration of drugs that are discussed in this chapter would provide an impetus to the researchers to design and develop better formulation of drugs or prodrugs.