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Chapter 2. Metabolism and Elimination
A. Liver is the primary site of drug metabolism.
First pass effect (or first pass metabolism) : metabolism of
a drug or other xenobiotic during the absorption process.
Typically in the liver or gastrointestinal tract after oral
administration.
The liver is a metabolic machine and often inactivates
drugs on their way from the GI tract to the body.
Some drugs (e.g. nitroglycerin) are not given orally but
by alternative route.
B. Metabolism can change a drug in several ways
1. The polarity is usually increased, enhancing the
water solubility and renal excretion of the drug
metabolite.
2. The activity of the drug is reduced. Exceptions are the
prodrugs, which are drugs that are inactive in the form
administered but are metabolized to their active forms.
Other examples of bioactivation:
prontosil/sulfanilamide;
methanol/formaldehyde,
salicin/salicylic acid--aspirin
Bonus-Credit for work out the detail reaction mechanism
3. Drug metabolites usually have smaller Vd
(apparent volume of distribution)
dose (mg)
Vd =
plasma concentration at equilibrium (mg/ml)
All biotransformation reactions can be assigned to one of two major
categories called phase I and II reactions
C. Phase 1 reactions are nonsynthetic.
1. Oxidation by mixed function oxidases (MFO) [also known as
cytochrome P-450s, microsomal enzymes, mono-oxygenases]
occurs in the smooth endoplasmic reticulum (ER). Important
exception (see below).
a. NADPH, cytochrome P-450 reductase, and O2 are required.
Drug +NADPH +H+ +O2  Drug-O+NADP + + H2O
b. Many reactions can be produced, including:
(1) hydroxylation
(2) dealkylation
(3) deamination
(4) sulfoxidation
(5) oxidation
Ethanol and caffeine
metabolized by enzyme
2. Reductions
present in soluble fraction
3. Hydrolysis
Examples of oxidative reaction
Examples of reduction reactions
Examples of hydrolysis reactions
D. Phase 2 reactions are conjugative (synthetic).
1. Glucuronidation occurs in the ER. Glucose is used to form
uridine diphosphate glucuronic acid (UDPGA) which then
transfers a glucuronide to the drug in the presence of glucuronyl
transferase.
2. Other substances can also be conjugated (by
transferases) to drugs, thereby reducing the drug activity,
including :
a. sulfate
b. acetyl
c. methyl
d. glutathione
e. amino acids, especially glycine
E. Factors affecting drug metabolism.
1. Enzyme induction. Some drugs (e.g. barbiturates,
phenytoin, rifampin, warfarin, alcohol) and pollutants (e.g.
cigarette smoke) increase the activity of drug-metabolizing
enzymes. Enzyme induced include: MFOs, glucuronyl
transferase, the steroid metabolizing system. This induction
hastens the metabolism of the inducing drug and many other
drugs.
self-induction, cross-induction.
case 1: coumadin (anticlotting drug) /phenobarbital
(sedative/hypnotic drug)
case 2: diphenylhydantoin (antiepilepsy drug)/ steroids (birth
control)
2. Enzyme inhibition. It can occur by decreased
synthesis of enzymes, increased degradation of the
enzyme, or competition of two or more drugs for the
same binding site. For example, cimetidine inhibits
the metabolism of several potentially toxic drugs
including phenytoin, warfarin and theophylline.
(Enzyme inhibition cont.)
-Liver cirrhosis, hepatotoxicants e.g. CCl4, toluene
-Virus infections, influenza A or adenovirus, may
affect the metabolism of theophylline (bronchodilator)
case in 1980 in Seattle
3. Genetic polymorphisms. The response to drugs varies
between individuals. Usually the variation shows the Gaussian
distribution, however, some drug responses show
discontinuous variation. For example, hepatic N-acetylase
displays genetic polymorphism. About 50% of the population
acetylate isoniazid (an anti- T.B. drug) rapidly, while the other
50% acetylate it slowly.
4. Age. Babies and the elderly show reduced hepatic metabolism
of drugs and the reduced renal mechanisms as well.
II. Excretion of drugs and drug metabolites
A.The kidney is the primary organ that excretes drugs and
drug metabolites.
1. Even when the drug is excreted in the unmetabolized form,
the kidney also decreases the pharmacological activity.
2. Polar drugs and polar drug metabolites are readily
eliminated by the kidney.
Nephron, the functional unit of kidney, approx. 1.2
million units in each man
Proximal tubule
Glomeruls
, to retain
plasma
proteins
Glomerular filtration
Cardiac output to kidney 20% approx. 1200 ml/min, I.e.
expose to 650 ml of plasma per min; normal rate of plasma
filtration 125 ml/min (the glomerular filtration rate) ,
the filration rate is plasma drug concentration independent
less than 50 kd molecules pass through
Serum creatinine is an
indicator
B. Filtration of the unbound molecule accounts for the
excretion of most drugs
1. Drug bound by plasma proteins will not be filtered by
the glomerulus.
2. Hydrophilic or lipophobic substances are most
efficiently eliminated by kidney, because they are not
readily reaborbed across the nephron tubule after they
are filtered.
3. If a drug is a weak base, administration of ammonium
chloride will acidify the urine and increase the amount of
the base that is in the ionized form.
a.The excretion of the weak base will be increased.
b.This will be most effective if the pKa of the drug is near the
physiological pH.
C. Active transport of a few drugs occurs in the
proximal tubule.
1. It usually involves secretion of strong acids or
strong bases.
2. Characteristics of active transport are:
a. competition between substrates for the carrier
b. saturation of the carrier
c. being unaffected by plasma protein binding
3. Active reabsorption can also occur.
4. A few substances are both actively secreted and
actively reabsorbed (e.g. uric acid, aspirin).
Blood vessel
 Tubular secretion
– Active transport, energy dependent secretory
process.
– is plasma drug concentration dependent
– is subjected to competition for transporter,
e.g. penicillin secretion can be interfered by
the co-administration of probenecid
(analgesic, anti-gout)
 Re-absorption
– is a passive process dependent on the lipid
solubility, pKa, pH, urine flow rate.
– The effect of urinary pH: In case of
phenobarbital ( a weak acid) overdose the
urine can be alkalinized by sodium
bicarbonate; Conversely, ammonium chloride
is used to acidify urine to increase the
excretion of basic drugs
D. Biliary excretion occurs in the liver
1. Large polar compounds, often conjugated metabolites,
are actively excreted into the bile.
important for elimination of compounds with a molecular
weight >500
2. Enterohepatic cycling occurs with a few drugs that
are eliminated in the bile, reabsorbed from the intestine,
returned to the liver and again eliminated in the bile.
liver
small intestine
a. glucuronidase in the intestine can cleave off the
glucuronide, so the free drug can be reabsorbed.
b. Digitoxin, a cardiac glycoside, undergoes enterohepatic
cycling.
c. This may increase the half-life of the drug.
Lung
1. the primary site of elimination for gaseous
anesthetics and volatile compounds.
2. ethanol : 90% metabolized in liver, 2% via lungs
equilibrium partition for ethanol between
blood and alveloar air is approx. 2100:1;
Thus, [ethanol] in blood = 2100 x [ethanol]
in end-expiratory air