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Drug metabolism Gastric emptying, law of mass action, 1st order, absorbance 1/2 life, elimination, 0 order, membrane perminisation of drugs, effects of ionisation, distribution, excretion, Questions With Complete Solutions

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Drug Metabolism

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Drug metabolism Gastric emptying, law of mass action, 1st
order, absorbance 1/2 life, elimination, 0 order, membrane
perminisation of drugs, effects of ionisation, distribution,
excretion, Questions With Complete Solutions

% of codeine converted to codeine 6-glucuronide by UGT2B7
or O-demethylated to morphine? Correct Answer 50-70% or 5-
15% - 200 fold more affinity for mu opiod receptor; converted
by CYP2D6

•63 year old male prescribed simvastatin 10mg daily. Over the
course of 3 months the patient did not respond to treatment so
dosage increased to 50mg daily.
•Patient later admitted to hospital with rhabdomyolysis.
-Breakdown of muscle tissue that leads to the release of muscle
fibre contents into the blood - harmful to kidney and causes
kidney damage. Why? Correct Answer •Patient had become
depressed and self administered St Johns Wort. He had stopped
treatment 10 days before toxicity occurred as he felt in improved
mood.
•What happened?
-Simvastatin: hyperlipidemic drug

,-St Johns Wort induces CYP450 3A4 - the main enzyme that
metabolises 50% types of drugs in liver.
•Therapeutic levels only achieved by increasing dose multiple
times
•The presence of another drug (herbal remedy) increased
clearance
•Alterations in plasma levels resulted in loss of efficacy/toxicity
•Toxic effects appeared gradually (days)
•Increased drug clearance was reversible
•Enzyme Induction: causes accelerated metabolism

Inducer brings about increase in synthesis of specific enzyme
isoform

•Catalyze the oxidation of a diverse array of lipophilic drugs,
steroids, thyroid hormones, fatty acids, and arachidonic acid
metabolites. Broadly characterized as: Correct Answer
NADPH + H+ + O2 + RH → NADP+ + H2O + ROH
•Catalysed by a mixed-function oxidase
•RH is a lipophilic substrate

,•ROH is a product (metabolite) that is more hydrophilic than the
substrate.

•Hypertensive drug
•Clinical importance: CYP2D6 involved in the metabolism of a
large number of commonly prescribed drugs.
•CYP2D6 pharmacogenetics may then become a useful tool to
predict drug-related side effects, interactions or therapeutic
failures.
•Hydroxylation catalyzed by CYP2D6
•Large inter-individual variation found; confirmed in twin
study's showing variability was genetic
•Bob Smith - St Mary's hospital - experimented on himself -
took dose and became dizzy, faint, severely hypotensive
Correct Answer Debrisoquine

•Phase 2 enzyme acetylates (N-acetyltransferase) isoniazid
•Antibiotic for tuberculosis: prodrug
•Slow acetylators - gene deletions (more likely to reach toxicity)
-40-60% Caucasian populations
->80% Middle Eastern populations

, -<20% Japanese populations
•Rapid acetylators - gene duplications (may not responds to drug
-too low conc)
-Inuit and Asians Correct Answer Isoniazid

•Significant clinical benefit in endocrine therapy
•Approximately 30-50% of the patients relapse or eventually die
from the disease
•The causes for breast cancer relapse are attributed to a variety
of factors, one of which may be traced to inter-individual
variability in CYP2D6 and its role in the formation of endoxifen
(very toxic) Correct Answer Tamoxifen

1/2 range of t 1/2 isoniazid Correct Answer 0.5 to 7.5 hours

A 29 year old healthy male took terfenadine
twice daily for allergic rhinitis. He had taken
the medication for one year. One day
the man took his tablets after two glasses of grapefruit juice
which he drank regularly. He went out to mow his lawn and
within one hour he had collapsed and died.

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Drug metabolism Gastric emptying, law of mass action, 1st order, absorbance 1/2 life, elimination, 0 order, membrane perminisation of drugs, effects of ionisation, distribution, excretion, Questions With Complete Solutions

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