Drug Metabolism 4

Why do foetuses express CYP isoforms distinct to adults?

Due to endobiotic metabolism

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What do the terms Km and Vmax mean?

Km is the concentration at half the maximum rate of reaction. Vmax is the maximum rate of reaction

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What are the complications of polypharmacy?

Drug-drug interactions affect concentrations of drugs (e.g. could lead to toxicity)

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What is single nucleotide polymorphism?

Change in allele, change in base sequence, changes protein sequence and formation of protein, affect metabolism (P450 polymorphisms)

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What are the three different types of coding sequence?

Synonymous (silent), non-synonymous (change one amino acid/reduce enzyme activity) and frameshift (complete change in base sequence/proteins not able to function)

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What is are the most important P450 enzymes?

CYP2D6 and CYP2C family

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What are the metabolic phenotypes?

Extensive metabolism (expected response). Intermediate metabolism (reduced level of activity/adverse effects/exaggerated toxicity). Poor metaboliser (drug has no effect/cannot be converted to active form

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Which types of alleles are affected by ethinicity?

CYP2D6 (other studies - CYP2C8 and CYP2C19 polymorphisms)

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Describe features of cyclophosphamide metabolism

Consequences of phase I metabolism, multiple enzymes requires. If one enzyme is removed, another pathway is used (reducing efficiency/toxicity)

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Are Phase II mutations important?

Not really e.g. another metabolic pathway can be used (glucuronidation not used but sulphonation can be used)

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Describe features of UGT1A1

Common in promoters. Crigler-Najjar-1 syndroe. CN-2 syndrone, Gilbert's syndroe (milkd, inability to glucuronidate bilirubin, most common polymorphism, 19% of some ethnic groups

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Describe features of geriatrics

Decline in renal function (decreased excretion), increase body fat (drug deposition), decrease in liver mass, decrease P450 function, decrease blood flow (reduce oxygen), reduce G.I.T blood flow

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Describe features of cirrhosis

Reduce blood flow (derangement of portal system/loss of functional hepatocytes), high extraction of drugs (clearance compromised/increase in bioavailability), low extraction drugs -reduce protein binding/albumin synthesis, increase in bioavailability

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Describe features of induction

Expression level of enzyme increased by endogenous/exogenous source (increase clearance, loss of therapeutic concentration, increase in toxicity if a produg, gradual effect. Phase I and II

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Describe features of inducers

Anticovulsants (phenytoin/carbamazepine/phenobarbitone), steroids (dexamethasone, prednisolone, glucocorticosteroids), polycyclic aromatic hydrocarbons (pollutants, smoke, solvents bbq meat), antibiotics (rifampicin, riseofulvin), nicotine, ethanol

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What is the effect of induction on clearance?

Increase clearance, decrease AUC/F/maximum concentration/half life (general clinical aspects)

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Describe features of inhibition

More potentially serious in clinical setting, reversible/irreversible. Examples of inhibitors are drugs, environmental compounds and diet

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Describe features of competitive inhibition

Substrate and inhibitor competes for active site. Km altered, Vmax remains the same

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Why do substances have the potential to inhibit drug metabolism?

Body cannot distinguish between compounds (compete for same pathway)

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What is the effect of inhibition on clearance?

Decrease clearance of drug, increase AUC/F/maximum concentration/half life

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Describe features of drug-drug interaction

Co-administration of one drug alters the metabolism of another (changes toxicity/clearance). Issue in polypharmacy (elderly/complex disease(

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Describe features of drug-diet interaction

Dietary constituents alter the metabolism of drug within the body. Less common. More serious consequences. Large volume of dietary compound saturates metabolic pathway, rapid increase in drug concentration (rapid onset toxicity)

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Drug Metabolism 4

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