Drug Metabolism II

usually expressed as a percentage of the amount of drug eliminated over the amount of drug that entered the organ. • e.g. 60mg of a drug enters the liver from the portal circulation. After first pass metabolism, only 10mg of the drug enters the systemic circulation. 50mg of the drug has been eliminated by the liver. The extraction ration is 50/60 = 83% • If there is a very small change in bioavailability, the oral dose of the drug approximates the IV dose (an IV dose of drug has a 100% bioavailability). • If the bioavailability is very small, virtually the entire drug is eliminated in the first pass effect, so that the oral dose must be much higher. Often, it is better to find alternative ways of administration to bypass the gut and liver. • E.g. Glycerol trinitrate is eliminated very rapidly by the liver, hence it is given sublingually.
• The veins under the tongue drain directly to the vena cava.
• Sometimes the first pass effect is useful • E.g. Salbutamol.
• Salbutamol is a beta2 agonist. We want it to work locally at the lungs, but sometimes salbutamol is swallowed (salbutamol is administered by a puffer).
• Salbutamol can thus enter the gut and passes through the liver.
• If salbutamol were allowed to enter the systemic circulation, it would have adverse effects on the heart.
• Luckily, salbutamol undergoes a large degree of first pass metabolism in the liver, so that the amount entering the systemic circulation is minimal.
• The following drugs have a high first pass clearance: • Aspirin • Morphine • Salbutamol • Verapamil Phase I reaction – Processes
• The main phase I reactions involve:
• Oxidation
 • Reduction
• Hydrolysis
• The most important phase I reaction is oxidation involving the mixed function oxidase system.
• This is an enzyme complex requiring:
• A reducing agent (NADPH)
• Molecular oxygen
• NADPH cytochrome p450 oxidase
• Cytochrome p450
• Many drugs can act to induce or inhibit the cytochrome p450 enzyme.
• Drugs which inhibit cytochrome p450 will prevent the metabolism of other drugs which rely on this enzyme. • E.g. Cimitidine blocks p450. If it is administered with digitoxin, digitoxin concentrations will remain high for longer periods.
Digitoxin is dangerous because it has a narrow therapeutic window, so any factors which could lead to an elevation of digitoxin levels is a potential hazard. • Drugs which induce the production of cytochrome p450 will accelerate the metabolism of drugs which rely on this enzyme.
• Examples of drugs which induce p450: • Polycyclic aromatic hydrocarbons • Glucocorticoids, macrolide antibiotics, anticonvulsants • Ethanol • Benzopyrene (found in cigarette smoke, a possible carcinogen when activated by the liver) • Barbituates (Phenobarbitone) • Hence, this is an important factor which needs to be kept in mind when using drug combinations • Mechanisms of induction (of cytochrome p450)
• Induction involves a drug binding to a cytosolic receptor.
• This drug-receptor complex is translocated to the nucleus where it stimulates the gene transcription and the increased production of protein.
• Mechanisms of inhibition (of cytochrome p450):
• Poorly understood
 • Probably via substrate competition
• A smoker can induce enzymes in the liver and also in other organs, thus increasing the metabolism and breakdown of drugs. Hence, it important to know whether a person is a smoker or not when prescribing drugs.

Phase II reactions – Processes• The enzymes involved in phase II reactions are all known as tranferases. • E.g. UDP-glucoronide transferase catalyses the conjugation of a drug with glucoronide. • If a toxic phase I product is produced, the body must rely on the phase II reaction to detoxify it. • Therefore, if a drug which has a toxic phase I product is taken at high doses, the liver will be unable to handle the increased levels of toxic products and hence will not be able to detoxify them in phase II reactions. The liver is dependent on the availability of endogenous molecules taking part in the detoxification reactions. • Conjugation usually allows for easier excretion since the drug is converted into a more hydrophilic form. Why is first pass clearance important? • Lets take an example of a drug which has a low extraction ratio by the liver: • E.g. Theophyline ER = 2% Bioavailability = 98% If liver enzymes are induced 2 fold ER = 4% Bioavailability = 96% • Now, lets take an example of a drug which has a high extraction ratio • E.g. Verapamil ER = 90% Bioavailability = 10% • If liver enzymes are induced 2 fold ER = 95% Bioavailability = 5% • What this shows is that for drugs with a low extraction ratio, a change in enzyme activity will lead to a small change in bioavailability. On the other hand, a drug which has a high extraction ratio will have a large change in bioavailability when enzyme activity is altered. • This means that, for high extraction drugs, liver enzyme activity is the major determinant of bioavailability.Drug – drug interactions • Some drugs may inhibit/induce the enzymes required for the metabolism of the other drug. Hence the clearance of the other drug may be reduced or increased respectively. • The oral does and IV dose is altered depending on bioavailability • For high bioavailability, oral dose » IV dose • For low bioavailability, oral dose > IV dose • Patients with liver disease will not metabolize drugs as effectively as someone with a healthy liver. • Other factors: • Age • Children may not yet have the full repertoire of enzymes required for metabolism Elderly people have a natural degradation of liver and renal function, hence leading to impaired clearance of drugs. • Some drugs may be stored in the liver, e.g. diazepam. Liver degradation can lead to reduced diazepam storage