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Drug Biotransformation

Elimination of the
Drug Biotransformation

Metabolism or
biotransformation -
complex of processes which provide
decreasing of toxicity and accelerate
excreting of the molecule of a drug or
other foreign substance after its
incoming into the organism
(Chemical alteration of the drug in the body )
Metabolism of Drugs
Aim: to convert non-polar lipid soluble
compounds to polar lipid insoluble
compounds to avoid reabsorption in renal
Most hydrophilic drugs are less
biotransformed and excreted unchanged
streptomycin, neostigmine and pancuronium
Biotransformation is required for protection
of body from toxic metabolites
Results of Biotransformation
Active drug and its metabolite to inactive
metabolites most drugs (ibuprofen,
paracetamol, chlormphenicol etc.)
Active drug to active product (phenacetin
acetminophen or paracetamol, morphine to
morphine-6-glucoronide, digitoxin to digoxin
Inactive drug to active/enhanced activity
(prodrug) levodopa - carbidopa,
prednisone prednisolone and enalapril
No toxic or less toxic drug to toxic
metabolites (Isonizide to Acetyl isoniazide)
Biotransformation of drugs into active (or
more active) metabolites
Initial drug Active metabolite
Allopurinol Aloxantin
Amitriptilin Nortriptilin
Acetylsalicylic acid Salicylic acid
Butadion Oxyfenbutazon
Diazepam Dismethyldiazepam
Digitoxin Digoxin
Codein Morphine
Cortizol Hydrocortizon
Methyldopa Methylnoradrenalin
Prednison Prednisolon
Novocainamid N-acetylnovocainamid
Propranolol N-oxypropranolol

muscle tissue
intestinal wall
Reactions of biotransformation
Nonsynthetic - phase metabolite may be
active or inactive

Synthetic - phase metabolites are

inactive (Morphine M-6 glucoronide is
phase (nonsynthetic reactions):
(oxydation, reduction, hydrolysis)

1) microsomal reactions
2) nonmicrosomal reactions
Reactions of phase - transformation in
molecule with formation of functional groups
with active hydrogen atom
Phase I - Oxidation

Most important drug metabolizing reaction

addition of oxygen or (ve) charged radical
or removal of hydrogen or (+ve) charged
Various oxidation reactions are
oxygenation or hydroxylation of C-, N- or S-
atoms; N or 0-dealkylation
Examples Barbiturates, phenothiazines,
paracetamol and steroids
Phase I - Oxidation
Involve cytochrome P-450 monooxygenases (CYP),
NADPH and Oxygen
More than 100 cytochrome P-450 isoenzymes are
identified and grouped into more than 20 families 1, 2
and 3
Sub-families are identified as A, B, and C etc.
In human - only 3 isoenzyme families important CYP1,
CYP2 and CYP3
CYP 3A4/5 carry out biotransformation of largest number
(3050%) of drugs. In addition to liver, this isoforms are
expressed in intestine (responsible for first pass
metabolism at this site) and kidney too
Inhibition of CYP 3A4 by erythromycin, clarithromycin,
ketoconzole, itraconazole, verapamil, diltiazem and a
constituent of grape fruit juice is responsible for
unwanted interaction with terfenadine and astemizole
Rifampicin, phenytoin, carbmazepine, phenobarbital are
inducers of the CYP 3A4
The catalytic cycle of
cytochrome P450
CYP-450 hemoprotein, which is able
to interact with substrate of
oxydation, to activate oxygen and
combine it with substrate.
Specifically on CY-450 reactions
of hydroxydation are performed
large amount of isoforms of this
enzyme possibility of its binding
with different substrates and
taking part in their metabolism
There are 24 isoforms of CY-450
in microsomes of human liver
Multiplicity of the enzyme has a
group character: one isoform of
CY-450 interacts not only with
one substrate but with a group of
Microsomal enzyme system

Oxydoreductases, esterases,
enzymes of proteins, lipids,
glycerophosphatides, lipo- and
glycoproteids, bile acids,
cholesterol, prostaglandins
biosynthesis, enzyme systems
of biosynthesis of couple
compounds, ethers of
glucuronic and sulfur acids
Oxydoreductases of microsomes (oxygenases of
microsomes, microsomal hydroxydating system, NADPH-
hydroxylase system,
monooxygenases of mixed functions)
these are enzymes which activate molecular oxygen and
catalize including of one (monooxygenase) or two
(dioxygenases) atoms of oxygen into molecule of substrate
(R) Reaction is presented as follows:
R + O2 + D = ROH + H2O + D
One atom of 2 is included into molecule of the substrate,
other is reduced to 2, therefore enzyme performs
oxygenase and oxydase functions simultaneously. Thats
why monooxygenases ate also called oxydases of mixed
function. Along with this hydroxyl group (-) forms in
molecule of substrate, thats why monooxygenase is also
calles hydroxylating system, and reaction of oxydation
oxydating hydroxylation
Nonmicrosomal Enzyme

Some Drugs are oxidized by non-

microsomal enzymes (mitochondrial
and cytoplsmic) Alcohol, Adrenaline,
Alcohol Dehydrogenase
Adrenaline MAO
Mercaptopurine Xanthine oxidase
Phase I - Reduction

This reaction is conversed of oxidation

and involves CYP 450 enzymes
working in the opposite direction.
Examples - Chloramphenicol,
levodopa, halothane and warfarin
Levodopa (DOPA) Dopamine DOPA-
Phase I - Hydrolysis

This is cleavage of drug molecule by taking

up of a molecule of water. Similarly amides
and polypeptides are hydrolyzed by amidase
and peptidases. Hydrolysis occurs in liver,
intestines, plasma and other tissues.
Examples - Choline esters, procaine,
lidocaine, pethidine, oxytocin
Phase II metabolism
Conjugation of the drug or its phase I metabolite with an
endogenous substrate - polar highly ionized organic acid to
be excreted in urine or bile - high energy requirements
Glucoronide conjugation - most important synthetic reaction
Compounds with hydroxyl or carboxylic acid group are easily
conjugated with glucoronic acid - derived from glucose
Examples: Chloramphenicol, aspirin, morphine,
metroniazole, bilirubin, thyroxine
Drug glucuronides, excreted in bile, can be hydrolyzed in the
gut by bacteria, producing beta-glucoronidase - liberated
drug is reabsorbed and undergoes the same fate -
enterohepatic recirculation (e.g. chloramphenicol,
phenolphthalein, oral contraceptives) and prolongs their
Phase II metabolism
Acetylation: Compounds having amino or
hydrazine residues are conjugated with
the help of acetyl CoA, e.g.sulfonamides,
Genetic polymorphism (slow and fast
Sulfate conjugation: The phenolic
compounds and steroids are sulfated by
sulfokinases, e.g. chloramphenicol,
adrenal and sex steroids
Phase II metabolism

Methylation: The amines and phenols can

be methylated. Methionine and cysteine act
as methyl donors.
Examples: adrenaline, histamine, nicotinic
Ribonucleoside/nucleotide synthesis :
activation of many purine and pyrimidine
antimetabolites used in cancer
Main ways of biotransformation of drugs
I phase
Oxydation: diazepam, pentazocin, sydnocarb, phenotiazin,
phenobarbital, aspirin, butadion, lidokain, morphin, codein,
ethanol, rifampicin
Reduction: hestagens, metronidazol, nitrazepam, levomycetin,
Hydrolysis: levomycetin, novocain, cocain, glycosides, ditilin,
novocainamid, xycain, fentanyl
II phase
Conjugation with sulfate: morphin, paracetamol, isadrin
Conjugation with glucuronic acid: teturam, sulfonamides,
levomycetin, morphin
Conjugation with remains of - aminoacids: nicotinic acid,
Acetylation: sulfonamides, isoniasid, novocainamid
Methylation: morphin, unitiol, ethionamid, noradrenalin
Metabolism in the intestinal
Synthetic and nonsynthetic reactions
take place
Isadrin conjugation with sulfate
Hydrlalasin - acetylation
Penicillin, aminazin metabolism with
nonspecific enzymes
Methotrexat, levodopa metabolism with
intestinal bacteria
Factors affecting

Concurrent use of drugs: Induction and

Genetic polymorphism
Pollutant exposure from environment
or industry
Pathological status
Factors that influence on drug metabolism
Factor Reaction type
Age (newborns, Decreasing of metabolism speed
children, elderly)
Pregnancy Increasing of metabolism speed
Genetic factor Various reactions
Liver pathology Decreasing of excreation speed of drugs, depending on their kinetics, type
and stage of liver disease, increasing of bioavailability and decreasing of
excretion speed of orally administered drugs with high hepatic clearence

GI pathology Changes in metabolism in GI epithelium

Nutrition Increasing of metabolism speed of certain drugs in case of diet with

character dominance of proteins and carbohydrates
Decreasing of metabolism speed in case of heavy digestive disorders linked
with starvation (total or protein)
Environment Increasing of metabolism speed if in contact
with chlorine insecticides
one time Depressing of enzymes that metabolise drugs
chronic Induction of enzyme system
Smoking Increasing of metabolism of certain drugs (i.e.
Way of Metabolism in liver before entering system
excretion circulation (first going-through effect) after
peroral administration of drugs
Time of Circade changes in drugs metabolism
introduction of
Interaction of Stimulation and depression of enzyme
drugs reaction

Absolutely contraindicated
Antibacterial: tetracyclins, levomycetin, fluoroquinolones,
sulfonamides, nalidixic acid, metronidazole
Antiviral: amantadin, gancyclovir, zidovudin, remantadin
Drugs effecting CNS: difenin, sodium valproate, lithium
preparations, barbiturates, reserpin, opioid analgesics (regularly)
Drugs of other groups: iodides, antithyroid drugs, undirect
anticoagulants, radiopharmaceutical drugs (radioactive iodine
etc.), Ergot alkaloids, chlorpropramid, cyclosporin

Bromides, meprobamat, derivatives of benzodiazepine
(diazepam, chlozepid, oxazepam etc.), aminazin,
M-cholinoblockers, glucocorticosteroids (if dosage is over
100 mg per day), indometacin, salycylates (large doses),
derivatives of sulfonilurea, theophyllin, chloroquin,
nitrofuran derivatives (furazolidon etc.), isoniazid,
cymetidin, aluminum containing antacids, estrogens,
gold medications, retinoids
Enzyme Inhibition

One drug can inhibit metabolism of other

if utilizes same enzyme
However not common because different
drugs are substrate of different CYPs
A drug may inhibit one isoenzyme while
being substrate of other isoenzyme
Some enzyme inhibitors Omeprazole,
metronidazole, isoniazide, ciprofloxacin and
Microsomal Enzyme
CYP3A antiepileptic agents - Phenobarbitone,
Rifampicin and glucocorticoide
CYP2E1 - isoniazid, acetone, chronic use of alcohol
Other inducers cigarette smoking, charcoal
broiled meat, industrial pollutants CYP1A
Consequences of Induction:
Decreased intensity Failure of OCPs
Increased intensity Paracetamol poisoning
Tolerance Carbmazepine
Some endogenous substrates are metabolized
faster steroids, bilirubin
Influence of body weight on kinetics
of drugs
In exhausted patients speeding up of
elimination, thats why it s appropriate to
introduce the increased dose 1+1/3
In patients with overweighting retention of
lipid-soluble drugs in the organism
For these patients its suitable to correct the dose
according to ideal body weight:
For men BW = 50 + [( - 150) : 2,5]
For women BW = 45 + [( - 150) : 2,5]
where height in cm
in case of normal body weight the dose is
calculated counting on 1 kg of patients body
Drug-Drug Interactions
during Metabolism
Many substrates are retained not only at the
active site of the enzyme but remain
nonspecifically bound to the lipid membrane
of the endoplasmic reticulum. In this state,
they may induce microsomal enzymes;
depending on the residual drug levels at the
active site, they also may competitively
inhibit metabolism of a simultaneously
administered drug.
Drug-Drug Interactions during
Enzyme-inducing drugs include various sedative-
hypnotics, tranquilizers, anticonvulsants, and
insecticides. Patients who routinely ingest barbiturates,
other sedative-hypnotics, or tranquilizers may require
considerably higher doses of warfarin (an oral
anticoagulant) to maintain a prolonged prothrombin
time. On the other hand, discontinuance of the sedative
may result in reduced metabolism of the anticoagulant
and bleedinga toxic effect of the ensuing enhanced
plasma levels of the anticoagulant. Similar interactions
have been observed in individuals receiving various
combination drug regimens such as antipsychotics or
sedatives with contraceptive agents, sedatives with
anticonvulsant drugs, and even alcohol with
hypoglycemic drugs (tolbutamide).
Drug-Drug Interactions during
Simultaneous administration of two or more
drugs may result in impaired elimination
of the more slowly metabolized drug and
prolongation or potentiation of its
pharmacologic effects
Both competitive substrate inhibition and
irreversible substrate-mediated enzyme
inactivation may augment plasma drug levels
and lead to toxic effects from drugs with
narrow therapeutic indices.
Drug-Drug Interactions during
Allopurinol both prolongs the duration and enhances the
chemotherapeutic action of mercaptopurine by
competitive inhibition of xanthine oxidase.
Consequently, to avoid bone marrow toxicity, the dose of
mercaptopurine is usually reduced in patients receiving
allopurinol. Cimetidine, a drug used in the treatment of
peptic ulcer, has been shown to potentiate the
pharmacologic actions of anticoagulants and sedatives.
The metabolism of the sedative chlordiazepoxide has
been shown to be inhibited by 63% after a single dose of
cimetidine; such effects are reversed within 48 hours
after withdrawal of cimetidine.

Presystemic elimination extraction of the

drug from blood circulatory system during
its first going through the liver (first pass
metabolism) it leads to decreasing of
bioavailability (and therefore, decreasing
of biological activity) of drugs

propranolol (anaprilin), labetolol,

aminazin, acetylsalicylic acid, labetolol,
hydralasin, isadrin, cortizone, lidokain,
morphin, pentasocin, organic nitrates,
Presystemic elimination
Clinical Relevance of Drug
The dose and the frequency of administration required
to achieve effective therapeutic blood and
tissue levels vary in different patients because of
individual differences in drug distribution and
rates of drug metabolism and elimination. These
differences are determined by genetic factors and
nongenetic variables such as age, sex, liver size, liver
function, circadian rhythm, body temperature,
and nutritional and environmental factors such as
concomitant exposure to inducers or inhibitors of
drug metabolism.
Elimination of the drugs

drugs can be excreted in forms of

metabolites or unchanged forms
through different ways: kidneys,
liver, lungs, intestines, sweat
and mammary glands etc.
Hydrophilic compounds can be easily
Elimination through kidneys
filtration, canalicular secretion and
canalicular reabsorption
filtration (relative molecular weight of drugs is less than 90,
if 90-300 with urine and bile): ampicillin, gentamicin,
urosulfan, novokainamid, digoxin
Disorders of filtration shock, collapse (due to decreasing
of blood circulation and hydrostatic pressure of blood
plasma in glomerular capillaries)
furosemide (closely connected with plamsa proteins) is not
filtrated in glomerular capilaries

canalicular secretion active process (with the aid of

enzyme system and using energy): penicillins,
furosemide, salicilates, chinin
Disorders of canalicular secretion in case of disorders of energetic
metabolism in kidneys: hypoxia, infections, intoxications
Glomerular Filtration

Normal GFR 120 ml/min

Glomerular capillaries have pores larger than usual
The kidney is responsible for excreting of all water
soluble substances
All nonprotein bound drugs (lipid soluble or
insoluble) presented to the glomerulus are filtered
Glomerular filtration of drugs depends on their
plasma protein binding and renal blood flow -
Protein bound drugs are not filtered !
Renal failure and aged persons
Tubular Re-absorption
Back diffusion of Drugs (99%) lipid soluble drugs
Depends on pH of urine, ionization etc.
Lipid insoluble ionized drugs excreted as it is
aminoglycoside (amikacin, gentamicin, tobramycin)
Changes in urinary pH can change the excretion
pattern of drugs
Weak bases ionize more and are less reabsorbed in
acidic urine.
Weak acids ionized more and are less reabsorbed in
alkaline urine
Utilized clinically in salicylate and barbiturate
poisoning alkanized urine (Drugs with pKa: 5 8)
Acidified urine atropine and morphine etc.
Tubular reabsorbtion
(reversed absorbtion)
lipid-soluble drugs are reabsorbed passively
ionized drugs, which are weak acids or alkali are
reabsorbed actively

regulation of level of reabsorbtion

- to speed up elimination of drugs weak alkalis
(antihistamine drugs, chinin, theophyllin) urine is made
acidic (with ascorbinic acid, ammonium chloride)
- to speed up elimination of drugs weak acids (NSAID,
including ASA, barbiturates, sulfonamides) urine is made
alkaline (introduction of sodium hydrocarbonate)
Tubular Secretion

Energy dependent active transport

reduces the free concentration of
drugs further, more drug dissociation
from plasma binding again more
secretion (protein binding is facilitatory
for excretion for some drugs)
with bile drugs and their metabolites with relative MM over
enterohepatic (intestinal-liver) recirculation:
cardiac glycosides, morphine, tetracyclines
are excreted with bile in unchanged condition (previously not
metabolized): antibiotics of tetracyclines group, macrolides
through lungs gases and volatile substances: ether for
narcosis, ftorotan, N2O, partly camphor, iodides, ethanol
through intestine: ftalasol, enteroseptol, magnesium sulfate
through sweat glands: iodides, bromides, salicylates
through bronchial, salivary glands: bromides, iodides
with milk: get into organism of the baby levomycetin,
fenilin, reserpin, lithium remedies, meprotan, tetracyclines,
sulfonamides etc.