# 10 - E. Metabolism of drugs

# E. Metabolism of drugs:

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for lithium carbonate or Clozaril vs. zaponex for clozapine. 
E. Metabolism of drugs: 
 Xenobiotics refer to the mechanism by which a foreign agent such as a drug molecule is 
metabolized and eliminated from our body. The metabolism or biotransformation of a drug 
renders it less lipid-soluble and more water-soluble. Therefore, the products of such metabolism 
are more readily eliminated from the body. 
The liver is the principal site of metabolism, but metabolism can occur in the gastrointestinal tract, 
plasma, lungs, kidneys, suprarenal cortex, placenta, skin, and lymphocytes. 
The four major metabolic routes are oxidation, reduction, hydrolysis, and conjugation. 
There are 2 phases of drug metabolism. 
 Phase 1 metabolism includes oxidation, reduction and hydrolysis (often mediated by CYP 
system, see below), as a result of which a molecule (could be active or inactive) suitable for 
conjugation is produced. It is not essential that a drug undergo phase 1 metabolism in 
order to undergo phase 2 metabolism e.g. lorazepam, temazepam and oxazepam undergo 
direct phase 2 reactions. (As a result, in patients with alcoholic liver disease, oxazepam is 
favoured for alcohol detoxification instead of chlordiazepoxide which requires intact liver 
enzymes for phase 1 clearance) 
 Phase 2 metabolism involves conjugation reactions such as glucuronidation, as a result of 
which polar compounds (mostly inactive) that are excretable in bile or urine are formed. 
A drug or drug metabolite from a phase 1 reaction is conjugated to a polar (water soluble) 
group by phase 2 metabolism. The result of this would be a water-soluble conjugate that 
can undergo renal excretion easily if it has a relative molecular mass of less than 300. If the 
relative molecular mass is more than 300, then the excretion would take place through bile. 
Metabolism usually yields inactive metabolites that are more polar and are easily excreted. 
Metabolism could also transfer some inactive pro-drugs into therapeutically active metabolites. 
Cytochrome P450 enzymes: Most psychotherapeutic drugs are oxidized by the hepatic 
cytochrome P-450 enzyme system. The human CYP enzymes comprise several distinct families 
and subfamilies. The most studied is CYP2D6. Together with CYP3A4, this constitutes nearly 90% 
of all psychotropic metabolism. 
The CYP enzymes are responsible for the inactivation of most psychotherapeutic drugs. These 
enzymes act primarily in the endoplasmic reticulum of the hepatocytes and cells of the intestine. 
Therefore, any cellular pathophysiology caused by viral hepatitis or cirrhosis may affect the

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efficiency of drug metabolism by the CYP enzymes. 
There are 3 ways in which drug interactions may influence the CYP system. It includes induction, 
non-competitive inhibition, and competitive inhibition. 
Genetic variations in the hepatic enzymes affect the rate of metabolism. Between 5 and 10% of 
Caucasians lack the enzyme CYP2D6 and are poor metabolizers of corresponding substrates. Up 
to 15-20% of East Asians are poor metabolizers of CYP2C19 substrates. 
The table below gives the list of some psychotropics with CYP-mediated drug interactions. Some 
of the important pharmacokinetic drug interactions involving psychotropics include 
 SSRIs especially fluvoxamine and fluoxetine inhibit CYP system. Fluoxetine increases 
plasma tricyclic antidepressants via 2D6 and 2C19. Fluvoxamine increases plasma 
clozapine concentrations. Clozapine levels may be increased 10-fold by the addition of 
fluvoxamine, which can induce seizures. 
 Carbamazepine decreases the plasma concentration of several drugs including 
contraceptive pills. 
 Most antidepressants can inhibit the metabolism of warfarin via a complex mechanism 
resulting in potentially serious bleeding. 
 Tricyclics and haloperidol compete with each other for same metabolic enzymes. 
 Carbamazepine and phenobarbitone can induce their own metabolism. 
 Alcohol, smoking and brussel sprouts are CYP inducers. Grapefruit juice and caffeine 
inhibit CYP system 
 
CYP enzyme 
Major psychotropics 
metabolized 
Effects of psychotropics 
CYP2D6 
All TCAs, fluoxetine, 
paroxetine, trazodone, 
nefazodone, valproate, all 
neuroleptics, risperidone. 
Paroxetine, to some extent fluoxetine, 
neuroleptics, amitriptyline and 
clomipramine inhibit 2D6. 
CYP3A4 (Most prominent in 
gut wall mucosa) 
Clomipramine, fluvoxamine, 
mirtazapine, nefazodone, 
Carbamazepine, most 
benzodiazepines. 
Stimulated by carbamazepine and 
barbiturates. Inhibited by calcium 
channel blockers, fluoxetine, and 
nefazodone. Smoking induces CYP1A2 
via PAH.

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Autoinduction: Carbamazepine is metabolized by the hepatic CYP2D6, synthesis of which in 
turn is induced by carbamazepine. As a result of this autoinduction, the rate of metabolism of 
carbamazepine (and other P450 substrates) gradually increases over the first several weeks of 
treatment. The initial steady state may be attained within 4 to 5 days, but autoinduction may 
delay final steady state until 3 to 4 weeks after treatment initiation. Hence, the level of 
carbamazepine must be monitored, and its dose often needs to be raised during this early phase 
of treatment. Chlorpromazine can also induce its own metabolism to some extent. 
Effect of smoking and caffeine: Smoking and caffeine 
affect glucuronidation reaction via UGT enzyme and 
CYP1A2. Drugs which are not dependent on CYP1A2 
or UGT for their metabolism are unaffected by smoking 
or caffeine consumption. For example, risperidone and 
aripiprazole (metabolized by CYP2D6 and CYP3A), 
quetiapine (mainly metabolized by CYP3A), and 
ziprasidone (mainly metabolized by an aldehyde 
oxidase and CYP3A) are unaffected. But the metabolism 
of clozapine and olanzapine is mainly dependent on 
CYP1A2 and UGTs. Because caffeine competitively 
inhibits CYP1A2, it increases the levels of clozapine and 
olanzapine while Polyaromatic Hydrocarbons (PAH) in 
cigarettes induce the enzyme. The effects of inhibitors 
(caffeine) are seen sooner than those of inducers 
(smoking), which require fresh synthesis of CYP1A2 
enzymes to produce an effect (de Leon, 2004). 
 
 
 
 
 
 
 
ALCOHOL BREAKDOWN 
 
Four distinct pathways for ethanol 
degradation have been described - 3 oxidative 
pathways and 1 non-oxidative pathway. 
 
Each of the oxidative pathways starts with 
the oxidation of ethanol to acetaldehyde, 
which is then oxidized to acetate for 
subsequent extra-hepatic activation to acetylCoA. The first pathway which contributes for 
>90% breakdown in Caucasians, utilizes 
cytoplasmic alcohol dehydrogenase, the 
second oxidative pathway uses the 
endoplasmic reticulum Microsomal Ethanol 
Oxidizing System (MEOS or CYP450 2E1) 
and the third pathway uses peroxisomal 
catalase. 
 
The nonoxidative pathway for ethanol 
metabolism is less well characterized but 
produces fatty acid ethyl esters (FAEEs) as 
primary end products.