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Metabolism and excretion: eliminating drugs from the body.

Stopping the action of a drug is an essential step in drug therapy. One of the key roles of the liver is to alter the chemical structure of foreign compounds--drugs and other toxins--allowing their excretion from the body. Drug metabolism occurs in two phases. These may be affected by developmental stage and age, by disease processes such as liver or heart failure or by the presence of other drugs or foods. Excretion of drugs is mainly through the kidneys and is also subject to variation.

Understanding the processes involved in drug elimination allows nurses to provide effective and safe care to patients with complex drug regimes.

INTRODUCTION

Effective drug therapy involves delivery of an active drug to its site of action (absorption and distribution), followed by inactivation and removal of the drug from the body (metabolism and excretion). The study of these processes is pharmacokinetics (see figure 1, right)--not to be confused with pharmacodynamics, which is the study of how a drug exerts its actions in the body. The aim of drug therapy is to provide optimal efficacy without causing toxicity. (1) To achieve this, drug entry into the body (dosage amount and timing) must be balanced with removal to maintain a plasma concentration above the minimum therapeutic level and below the minimum toxic level.

The rate at which a drug is inactivated directly affects its concentration in the plasma. Some drugs are eliminated via the kidneys unchanged, so do not undergo metabolism, but most require some chemical change to be removed from the plasma. Metabolism of drugs occurs mainly in the liver, but may also occur in the kidneys, lungs, gastrointestinal (GI) tract and the plasma. Excretion of drugs is largely through the kidneys, but may also occur via the GI tract, lungs and sweat. This article addresses key aspects of liver metabolism and the factors that may affect these, and the components of renal and hepatobiliary (GI) excretion.

METABOLISM IN THE LIVER

The majority (75 per cent) of drugs are lipid soluble, which allows ready absorption and distribution throughout the body. However, it also prevents elimination, as drugs filtered at the glomerulus can freely cross back into the plasma from the urinary filtrate. Drug metabolism is the biotransformation of lipid-soluble chemicals into water-soluble forms that allow their excretion in the urine. Biotransformation occurs in two phases. Drugs may undergo one phase only, or be metabolised through both phases sequentially. Biotransformation of drugs may, depending on the drug involved, result in a number of outcomes (see figure 2, p21). (1)

Phase I metabolism

During phase I metabolism, drug molecules are transformed through oxidation or reduction of hydrolysis reactions by the action of a family of enzymes called the Cytochrome P450 (CYP) or microsomal enzyme system. These enzymes are found in hepatocytes and in most body cells, especially in the GI tract, kidneys and lungs. Drugs must cross the cell membrane to access these enzymes, meaning that lipid-soluble drugs are more likely to be metabolised in this way. (2) There are many CYP enzyme sub-families. Those most important in drug metabolism are CYP1, CYP2 and CYP3; out of these, six enzymes are responsible for the biotransformation of more than 90 percent of drugs undergoing phase I metabolism (see table 1, p22). (3)

[FIGURE 1 OMITTED]

The genes for the CYP enzymes are subject to polymorphism: multiple genetic variants occur for the genes. This causes different phenotype expression, affecting the rate at which drugs may be metabolised by an individual: (1)

* Two normal genes [right arrow] extensive metaboliser.

* One normal and one variant gene [right arrow] intermediate metaboliser.

* Two variant genes [right arrow] poor metaboliser.

* Duplication of normal genes [right arrow] ultrafast metaboliser.

The two enzymes most particularly affected are CYP2D6 and CYP2C19. (3) For drugs inactivated by the CYP enzymes, poor metabolisers will be slow to clear the drug and risk toxicity, while ultrafast metabolisers will clear the drug too rapidly and may not achieve therapeutic plasma concentrations (see box 1, p22). (4)

CYP enzymes are also subject to induction and inhibition by other compounds. An inducer is a drug that triggers the synthesis of more of a specific enzyme. This increases the rate at which substrate drugs are metabolised. The active drug may be metabolised and cleared too rapidly from the plasma to achieve adequate concentrations, so therapeutic failure may occur. In the case of a pro-drug (one that is administered in an inactive form and must be metabolised in the body to start working), enzyme induction will cause rapid activation and may lead to toxicity. St John's Wort is an inducer of the CYP3A4 enzyme and can reduce the efficacy of numerous drugs when taken as a "natural" remedy for depression. Other inducers of P450 enzymes are brussels sprouts and cigarette smoke. Rapid metabolism of a drug may also lead to excess accumulation of toxic metabolites.

Enzyme inhibitors, as the name suggests, block the action of the enzyme. In this case, substrate drugs are poorly cleared from the plasma, increasing the risk of toxicity. A key example of the dangers of this type of drug interaction is the combination of simvastatin and inhibitors of the CYP3A4 enzyme, such as the antifungal drug itraconazole. The increased concentration of simvastatin can cause myopathy or even rhabdomyolysis (destruction of skeletal muscle). Toxic levels of simvastatin cause damage to myocytes that lead to disruption of the membrane and release of myoglobin into the circulation. The excess myoglobin precipitates in the kidneys, causing acute kidney injury and may also induce disseminated intravascular coagulation. Patients present with severe muscle weakness and pain, with dark urine. (5)

The outcome of phase I metabolism is a drug molecule that is able to be conjugated (joined) with another molecule during phase two. Often this molecule is pharmacologically inactive but more chemically reactive than the parent drug, and may be toxic or even carcinogenic (see box 2, p23).

Phase II metabolism

Some drugs are able to be excreted immediately following phase I metabolism. However, water solubility is not achieved in many drugs until the drug or its reactive phase I metabolite is joined to another polar molecule by phase II conjugation. Addition of a large polar molecule to a drug molecule makes it less likely to be reabsorbed from the renal tubules, following its filtration at the glomerulus.

Conjugation occurs mainly in the liver, and most conjugation reactions involve the attachment of a glucuronide molecule to the drug. The resultant metabolite is normally inactive, although there are exceptions to this, such as morphine-6-glucuronide, which has stronger analgesic effect than morphine itself. (2)

First pass metabolism

Orally administered drugs pass through the liver before entering the systemic circulation. These drugs are therefore subjected to biotransformation processes in the liver (and in the gut wall) before they get a chance to exert their therapeutic effects. Drugs that are readily metabolised may not reach the systemic circulation at all, or they may require very high oral doses to overcome this effect.

[FIGURE 2 OMITTED]

Glyceryl trinitrate (GTN)--used to treat angina--is so extensively metabolised that it cannot be given orally, and is therefore administered sublingually to avoid first-pass metabolism. Other drugs subject to extensive first-pass extraction include morphine, tricyclic antidepressants, statins, some beta-blockers and the selective serotonin reuptake inhibitors (SSRIs). (1) These drugs will always be given in much lower doses when administered via parenteral routes (ie not via the GI tract). Caution should be taken in patients with liver disease, where the amount of drug eliminated during first pass may be decreased, thus increasing the risk of toxicity.

Grapefruit juice is an inhibitor of CYP3A4, acting mainly on enzymes within the gut wall. This decreases the amount of drug that is removed during first-pass metabolism, and may cause significant toxicity. Drugs affected by grapefruit juice, where there is a clinically significant risk, include the statins, felodipine and other calcium antagonists, cyclosporin, and amiodorone. (1,6) Moderate intake of grapefruit juice only affects the CYP3A4 enzymes in the gut wall. Excessive consumption (three or more glasses per day) may also inhibit hepatic enzymes. The effect of ingestion may last up to three days from a single glass of juice, because the furanocoumarins in the juice bind to, and irreversibly inhibit, CYP3A4 molecules. The enzymes must therefore be replaced with newly synthesised molecules. (6)

Zero and first-order kinetics

Most drugs are metabolised by first-order kinetics: the rate of elimination is proportional to the concentration of the drug. As the concentration of the drug increases, so does the rate at which the drug is metabolised. As the metabolising enzymes become saturated, metabolism switches to zero-order kinetics (where the drug is eliminated at a constant rate, regardless of concentration). However, a very few drugs (eg aspirin, phenytoin), taken at therapeutic doses, will saturate their enzymes. These drugs then enter zero-order kinetics and their steady-state plasma concentrations are highly variable and difficult to predict. Metabolising of alcohol (ethanol) provides a key example of zero-order kinetics (see box 3, p23).

Excretion of drugs

Drug excretion is the removal of a drug, or its metabolites, to the external environment, and occurs mainly in the kidneys. The liver is involved in drug excretion through the hepato-biliary route. Other sites of drug excretion--eg lungs, sweat glands, tears, saliva and vaginal secretions--are minor and are not generally considered in discussions of excretion. An exception to this is breast milk, where the excretion of drugs may affect the baby (see box 1, right). (7)

Renal excretion

The kidneys' handling of drugs occurs through three processes: glomerular filtration, tubular reabsorption and tubular secretion.

Glomerular filtration: As blood passes through the glomerulus, components are filtered to form the renal filtrate. Large molecules cannot be filtered through the glomerular membrane, ensuring that large drugs (eg heparin) and plasma proteins do not normally cross. Drugs bound to plasma proteins for transport also cannot cross into the filtrate. These restrictions on filtration mean while some drugs or their metabolites pass freely into the filtrate and may be excreted rapidly, others may be excreted very slowly.

Warfarin is a highly protein-bound drug (approximately 98 per cent of the drug is bound to plasma proteins). Only the unbound drug--two per cent--can be filtered, so clearance by filtration is reduced, in comparison to an unbound drug. (2)

Once filtration occurs, a drug may stay in the filtrate, to be excreted in the urine, or it may be reabsorbed from the filtrate as it moves along the renal tubules.

Tubular reabsorption: Water solubility determines the extent to which reabsorption from the tubules occurs. About 99 per cent of substances filtered at the glomerulus are reabsorbed along the renal tubules. Therefore the majority of filtered, unmetabolised drug molecules are also reabsorbed. A drug (or metabolite) that is water soluble cannot be reabsorbed following filtration or secretion, because to do so it must cross the membranes of the cells lining the tubules. Only lipid-soluble substances are able to do this. Water-soluble drugs, such as gentamycin, furosemide, methotrexate, benzylpenicillin and digoxin, are therefore excreted unchanged in the urine because they do not need to undergo biotransformation to increase their water solubility.

Water solubility can be increased to prevent reabsorption of drugs by altering the pH of the renal filtrate: drugs lose their lipid-solubility when they become ionised. An acidic drug placed in an alkaline environment will become less lipid soluble, and the same occurs for alkaline drugs in an acidic environment. This is a useful therapeutic tool: (1)

* In aspirin overdose, alkalinising the urine increases rate of excretion of salicylate.

* Amphetamine excretion is increased if the urine is acidified.
Box 1. Taking codeine? Ethnicity matters

Codeine is a pro-drug, ie it relies on biotransformation to its
active form--morphine--for analgesic effect. The enzyme required
for this conversion is CYP2D6, which is subject to genetic
polymorphism. Up to 10 percent of people of European descent, and
three per cent of Asians, Africans and Maori and Pacific peoples,
are poor metabolisers at CYP2D6. For poor metabolisers, codeine is
ineffective as an analgesic, as it is not converted to morphine in
sufficient concentrations to provide pain relief.

In contrast, up to 16 per cent of northeast Africans/Saudi Arabians
and two to five per cent of other ethnicities are classed as
ultra-rapid metabolisers at CYP2D6. This raises the risk of
excessive exposure to morphine. In 2007, a baby in Toronto, Canada,
died of morphine poisoning. The mother had been prescribed
paracetamol and codeine for postpartum analgesia. As a rapid
metaboliser, she processed the drug to morphine more rapidly and in
larger concentrations than normal, and the baby received an
overdose in the breast milk.

Box 2. Paracetamol poisoning (2,4)

The majority of paracetamol (90 per cent) is normally metabolised
in the liver, via phase II conjugation with glucuronide or sulphate
molecules. The remaining 10 per cent undergoes both phase I and
phase II biotransformation. If plasma concentrations are greater
than normal (greater than 10g/24 hours in an adult), conjugation
pathways become saturated and phase I metabolism increases. CYP1A2
and 2E1 enzymes convert paracetamol into the highly reactive and
toxic metabolite N-acetyl-p-benzoquinone imine (NAPBQI). This
occurs at a more rapid rate when there has been enzyme induction
due to, for example, chronic alcohol use.

Initially, NAPBQI is rapidly inactivated by phase II conjugation
with glutathione. However, once stores of glutathione are depleted,
NAPBQI reacts with cell structures within the hepatocytes. The
generation of reactive oxygen species, disruption of protein
structure and function, and other effects cause death of the
hepatocytes and may lead within 24-48 hours of overdose, to liver
failure and possibly death, although this is relatively rare.

Intravenous infusion of acetylcysteine or oral adminsitraiton of
methionine can increase the amount of glutathione available for
conjugation with NAPBQI. However, these must be administered within
12 hours of ingestion of paracetamol to be truly effective. Excess
ingestion of paracetamol is the commonest form of drug poisoning
and may occur as a result of accidental ingestion in children, or
deliberate or accidental overdose in adults. The risk of accidental
overdose is increased with the availability of combination
cold-and-flu remedies containing paracetamol.


Some substances are actively reabsorbed from the urinary filtrate and drugs can be used to inhibit this process: the drug probenecid, used to treat gout, inhibits the reabsorption of uric acid.

Tubular secretion: Active secretion into the renal tubules occurs for some drugs that are not readily filtered in the glomerulus. This highly efficient active transport process can ensure almost complete clearance of drugs such as penicillin. Other drugs excreted by this process include non-steroidal anti-inflammatory drugs and methotrexate.

Drugs may compete with each other for the transport sites. This may be therapeutically useful: probenecid (described above) inhibits the renal secretion of penicillin, increasing its half-life and prolonging its action in the body. In other cases, competition for transport sites can cause increased morbidity: aspirin can inhibit the secretion of uric acid, aggravating gout.

Drugs competing for the same transporter mechanism may have prolonged clearance, with potential for increased toxicity. Digoxin is a basic drug secreted unchanged into the urine by the p-glycoprotein transporter. Other drugs that compete for the same transporter include spironolactone, verapamil and amiodorone. Digoxin has a narrow therapeutic window, so any decrease in secretion carries a high risk of toxicity. (2)

Hepatobiliary excretion

Similar transport mechanisms are used in the liver to secrete drugs into the bile, allowing them to be excreted in the faeces. A number of drugs that have been conjugated with glucuronide during phase II metabolism are excreted into the bile by these mechanisms.

On entering the GI tract with the bile, glucuronide may be removed by enzymes produced by the resident bacteria of the lower small intestine and colon, and the now-active drug is able to be reabsorbed. Thus a reservoir of the drug is established in the enterohepatic circulation, with an ongoing cycle of absorption, metabolism, secretion into the bile and reabsorption. Up to 20 per cent of the total drug in the body can be involved in this process, delaying drug clearance. This effect is allowed for in the calculation of drug doses when it is recognised, eg the active metabolite of morphine--morphine-6-glucuronide--is recirculated (see box 4, p24). (8)

DRUG CLEARANCE

Drug clearance refers to the rate at which drugs, or their active metabolites, are permanently removed from the circulation. (1) The factors that affect clearance are:

* Liver function (metabolism and excretion)

* Renal function (excretion)

* Volume of distribution of a drug In turn, clearance determines drug half life--increased clearance means a decreased half-life.

Volume of distribution affects drug clearance because only drug in the plasma is able to be transported to and cleared by the liver and kidneys. A drug that is widely distributed in the body will take longer to reach the organs of elimination.

A good example of this effect is found in the benzodiazepine drugs. Following absorption, benzodiazepines are distributed throughout the body and slowly accumulate, preferentially in body fat stores. Many in this class of drugs have active metabolites that also accumulate. Thus the clearance of many benzodiazepines is slow and unpredictable, and half-life may be very prolonged. This is of particular relevance in older adults where the proportion of fat to water in the body is greater, and where phase I liver enzyme function may be reduced. Prolonged half-life and reduced clearance can lead to drowsiness and confusion, frequently mistaken for the normal effects of ageing. (2)
Box 3. Alcohol

Alcohol is eliminated from the body by zero-order kinetics: the
elimination of alcohol proceeds at the same rate, independent of
intake or the plasma concentration--about 15mg/100ml of plasma per
hour*. (1) Therefore, the more alcohol ingested, the longer the
elimination process. This occurs because the enzyme responsible for
phase I oxidation of ethanol--alcohol dehydrogenase--is readily
saturated. Therefore three standard drinks would take a minimum of
four hours (in a large male) to be eliminated from the body. This
is the reason it is still possible to be over the legal alcohol
limit, the morning after a drinking session. The metabolism of
alcohol occurs in two steps:

[ILLUSTRATION OMITTED]

Up to 50 per cent of Asians have a variant gene for aldehyde
dehydrogenase, which is non-functional. This causes acetaldehyde to
accumulate after ingesting ethanol, leading to facial flushing,
dizziness, nausea and vomiting. It may also lead to an increased
risk of oesophageal and stomach cancers. The accumulation of
acetaldehyde is also blamed for hangover symptoms. Disulfram, used
in the treatment of alcoholism, acts by inhibiting this aldehyde
dehydrogenase.

* Note that the current legal driving limit for blood alcohol is 80
mg/100ml of plasma. One standard drink has about 10g of ethanol,
giving a plasma concentration of 20-50mg/100ml (depending on gender
and size).

Box 4. Oral contraceptives

The oestrogen component of oral contraceptive drugs is subject to
enterohepatic recycling in variable amounts. This recycling is
taken into account when formulating the drug regime. Some
antibiotics may reduce the amount of the drug reabsorbed by this
mechanism and, in theory, lead to contraceptive failure.
Broad-spectrum antibiotics destroy the normal flora of the gut.
There is anecdotal evidence to suggest this affects the
enterohepatic recycling of oestrogens and may have an impact on the
reliability of the contraceptive pill. Women have, in the past,
been advised to use alternative forms of contraception while taking
antibiotics and for one week after. The evidence of antibiotics
having this effect is weak, and guidelines from the World Health
Organisation and others say these precautions are not necessary,
unless the course of antibiotics is longer than three weeks, or if
the antibiotics are specific enzyme inhibitors (eg rifampicin). (8)


Liver function and clearance

As the main site for drug metabolism, the liver can have a profound impact on drug clearance. There are two main mechanisms by which liver metabolism may be impaired:

* Decreased enzyme activity

* Decreased or impaired liver blood flow

Enzyme activity: Enzyme activity may be decreased in many liver diseases, and is also affected by age and developmental stage. The main impact of liver disease is on phase I enzymes, which will affect both clearance and first-pass metabolism. Cirrhosis has the most effect on drug metabolism. (9) Advanced liver disease will also impair phase II metabolism.

In children, there are significant differences in both phase I and phase II metabolism. Neonates have reduced function in CYP450 enzymes and in conjugation reactions. The major CYP enzyme in infants up to six months of age is CYP3A7, and the actions of this enzyme in relation to substrates, inhibitors and inducers is not well studied. (10) As a child develops, there are variable increases in the levels of the other CYP enzymes. Most have attained adult concentrations at about two years of age, but CYP2D6 does not reach adult levels until about age 12. The same occurs with a number of the phase II conjugating enzymes where adult function is not achieved until 11-13 years of age. Extrahepatic metabolising enzymes are similarly affected. (10)

Older adults have variable decline in enzyme function, although some of the evidence is contradictory. Generally there are mild declines in all aspects of drug metabolism, but this may be accelerated by conditions that impair blood and nutrient flow to the liver.

Liver blood flow: Impaired blood flow to the liver, or shunting within the liver (arising from fibrosis in liver disease) decrease the rate of delivery of oxygen and nutrients and may impair liver enzyme function. It will also decrease the delivery of drugs for metabolism and may thus impair clearance and prolong half-life. Cardiovascular disease with reduced cardiac output, eg congestive heart failure, is the main cause of declining hepatic blood supply. Drugs that are particularly affected are those with a high hepatic clearance and high first-pass metabolism. All antipsychotics, calcium antagonists, statins, tricyclic antidepressants and SSRIs are included in this category, as well as many anti-arrhythmics, beta-blockers and opioid drugs. (1)

Renal function and clearance

About 25 per cent of drugs are excreted through the kidneys without being first metabolised. Clearance of these drugs is directly related to creatinine clearance. If renal function is decreased, so too is the clearance of these types of drugs. For many other drugs where biotransformation in the liver results in inactive metabolites, renal function is not as important in clearance, since the drug is already inactive prior to excretion. Other drugs that have active metabolites must be used with caution.

Low renal filtration volumes can delay drug clearance. Firstly, this is indicative of low blood flow through the glomerulus, so drugs are not being delivered for filtration. Secondly, low filtrate volume causes increased concentration of the drug in the renal filtrate. Reabsorption of drugs is a passive process down a concentration gradient, and high concentration in the filtrate causes increased reabsorption of lipid-soluble drugs.

Drugs that should be administered with caution in renal impairment fall into two categories: those with a moderate renal clearance but narrow therapeutic window (eg gentamycin, enalapril, digoxin), and those with wide therapeutic windows but high renal clearance (eg atenolol, penicillin, cephalosporins, enoxaparin). (1) Renal function declines with age, so the drugs described above should be administered with caution in older adults, regardless of health status. The increased volume of distribution for lipid-soluble drugs in the elderly, combined with decreased clearance, leads to prolonged half-life for many drugs.

Renal clearance up to six to 12 months of age varies considerably, compared with adults. In the neonate, clearance is about 20 per cent of adult values and drug elimination is thus greatly reduced.2 Body water content is higher proportionally than fat, so drug distribution is also altered. Half-lives of drugs must be carefully considered before administering to infants.

CONCLUSION

Pharmacokinetics can be complex for individual drugs, and this complexity only increases where there is a multiple medication regime. Knowledge about the potential impact of age, developmental stage, disease and other drugs on metabolism and excretion of drugs can help nurses provide safe care. Essential to this care is assessment of the effectiveness of a regime, monitoring for adverse effects, and providing education and support to patients, enabling them to manage and make decisions about their drug treatment.

LEARNING OUTCOMES

After reading this article and completing the accompanying online learning activities, you should be able to:

* Describe the events occurring during phase I and phase II metabolism.

* Describe how the kidneys handle drugs and factors that affect drug excretion.

* Discuss the effects of developmental stage, ageing and disease on drug metabolism and excretion.

* Outline examples of types of drug-drug and drug-food interactions that affect elimination of drugs.

References

(1) Begg, J. (2008) Instant clinical pharmacology (2nd ed). Oxford: Blackwell Publishing.

(2) Rang, H. et al. (2012) Rang and Dale's Pharmacology (7th ed). Edinburgh: Churchill Livingstone.

(3) Lynch, T. & Price, A. (2007) The effect of cytochrome P450 metabolism on drug response, interactions and adverse effects. American Family Physician; 76: 3, pp390-396.

(4) Daly, F. et al. (2008) Guidelines for the management of paracetamol poisoning in Australia and New Zealand--explanation and elaboration. Medical Journal of Australia; 188: 5, pp296-302.

(5) Muscal, E. (2012) Rhabdomyolysis. Medscape Reference. http://emedicine.medscape.com/ article/1007814-overview. Retrieved 15/7/12.

(6) Hanley, M. et al. (2011) The effect of grapefruit juice on drug disposition. Expert Opinion on Drug Metabolism & Toxicology; 7: 3, pp267-286.

(7) Casey, G. (2012) Breastfeeding and drugs. Kai Tiaki Nursing New Zealand; 18: 2, pp20-24.

(8) Faculty of Sexual and Reproductive Healthcare. (2011) Drug interactions with hormonal contraception. London: Royal College of Obstetricians and Gynaecologists.

(9) Verbeeck, R. (2008) Pharmacokinetics and dose adjustment in patients with hepatic dysfunction. European Journal of Clinical Pharmacology; 64, pp1147-1161.

(10) Strolin Benedetti, M., Whomsley, R. & Canning, M. (2007) Drug metabolism in the paediatric population and in the elderly. Drug Discovery Today; 12: 15/16, pp599-610.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Table 1. Drugs commonly metabolised by CYP450 [enzymes.sub.2,3]

P450      Examples of          Examples of          Examples of
Enzyme    substrate drugs      inhibitors           inducers

CYP1A2    Paracetamol,         Amiodorone,          Tobacco
          caffeine,            cimetidine,
          clozapine,           ciprofloxacin
          warfarin

CYP2C19   Omeprazole,          Moclobemide,         Phenytoin,
          phenytoin            chloramphenicol      carbamazepine

CYP2C9    Warfarin,            Amiodorone,          Phenytoin,
          glipizide,           -azole drugs,        carbamazepine
          losartan*            fluoxetine

CYP2D6    Codeine *,           Amiodorone,          None
          tramadol,            cimetidine,
          metoprolol,          fluoxetine
          amitriptyline,
          haloperidol,
          warfarin

CYP2E1    Paracetamol,         Disulfram            Ethanol
          ethanol,
          inhalation
          anaesthetics

CYP3A4    Simvastatin, most    Grapefruit juice,    St John's Wort,
          benzodiazepines,     diltiazem, -azole    carbamazepine,
          sildenafil,          antifungal drugs,    phenytoin
          warfarin             erythromycin

* pro-drug
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Title Annotation:CONTINUING PROFESSIONAL DEVELOPMENT
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Report
Geographic Code:8NEWZ
Date:Aug 1, 2012
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