Download Metabolism of drugs

Drug Biotransformation
Elimination of the
drugs
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 tubules
• Most hydrophilic drugs are less biotransformed and
excreted unchanged – streptomycin, neostigmine
and pancuronium etc.
• 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 etc.)
• Inactive drug to active/enhanced activity
(prodrug) – levodopa - carbidopa, prednisone –
prednisolone and enalapril – enalaprilat)
• No toxic or less toxic drug to toxic metabolites
(Isonizide to Acetyl isoniazide)
Biotransformation of drugs into active (or
more active) metabolites
Initial drug
• Allopurinol
• Amitriptilin
• Acetylsalicylic acid
• Butadion
• Diazepam
• Digitoxin
• Codein
• Cortizol
• Methyldopa
• Prednison
• Novocainamid
• Propranolol
Active metabolite
• Aloxantin
• Nortriptilin
• Salicylic acid
• Oxyfenbutazon
• Dismethyldiazepam
• Digoxin
• Morphine
• Hydrocortizon
• Methylnoradrenalin
• Prednisolon
• N-acetylnovocainamid
• N-oxypropranolol
ORGANS OF DRUGS METABOLISM
•liver
• kidneys
• muscle tissue
• intestinal wall
• lungs
• skin
• blood
Reactions of biotransformation
• Nonsynthetic - І phase – metabolite may be active or
inactive
• Synthetic - ІІ phase – metabolites are inactive
(Morphine – M-6 glucoronide is exception)
І phase (nonsynthetic reactions):
(oxydation, reduction, hydrolysis)
• 1) microsomal reactions
• 2) nonmicrosomal reactions
Reactions of І 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 radical
• Various oxidation reactions are – oxygenation or
hydroxylation of C-, N- or S-atoms; N or 0dealkylation
• 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 (30–
50%) 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 CYР-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 CYР-450 in
microsomes of human liver
Multiplicity of the enzyme has a group
character: one isoform of CYР-450
interacts not only with one substrate
but with a group of substances
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 + DН = ROH + H2O + D
One atom of О2 is included into molecule of the substrate, other
is reduced to Н2О, therefore enzyme performs oxygenase and
oxydase functions simultaneously. That’s why monooxygenases
ate also called oxydases of mixed function. Along with this
hydroxyl group (-ОН) forms in molecule of substrate, that’s why
monooxygenase is also calles hydroxylating system, and reaction
of oxydation – oxydating hydroxylation
Nonmicrosomal Enzyme Oxidation
• Some Drugs are oxidized by non-microsomal enzymes (mitochondrial
and cytoplsmic) – Alcohol, Adrenaline, Mercaptopurine
• 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-decarboxylase
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
1- Esterase enzymes:
• Usually present in plasma and various tissues, are nonspecific and catalyze deesterification. Hydrolysis of nonpolar esters into two polar and more water soluble
compounds (i.e. acid and alcohol).
O
O
CH3
CH3
C OR + H2O
Ester of acetic acid
C OH + ROH
Acetic acid
Alcohol
Esterases are responsible for converting many prodrugs into
their active forms.
A classical example of ester hydrolysis is the metabolic
conversion of aspirin (acetylsalicylic acid) to salicylic acid and
COOH
acetic acid.
COOH
OCOCH3
H2O
OH
+
CH3COOH
Acetic acid
Aspirin
Salicylic acid
2-Amidase enzymes:
It is the hydrolysis of amides into amine and acid and this is called
Deamination.Deamination occurs primarily in the liver.
O
O
NH2
C R
Amide
+ H2O
Water
R C OH + NH3
Acid
Ammonia
•Amide drugs are more resistant to hydrolysis (or they are not
hydrolyzed until they reach the liver) than ester drugs which
they are susceptible to plasma esterase.
•The duration of actions of ester drugs are less than the
amide analogues.
Example:
Procaine (ester type) injection or topical is usually shorter
acting than its amide analogue procainamide administered
similarily.
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 action
Phase II metabolism – contd.
• Acetylation: Compounds having amino or hydrazine residues are
conjugated with the help of acetyl CoA, e.g.sulfonamides, isoniazid
• Genetic polymorphism (slow and fast acetylators)
• Sulfate conjugation: The phenolic compounds and steroids are
sulfated by sulfokinases, e.g. chloramphenicol, adrenal and sex
steroids
Phase II metabolism – contd.
• Methylation: The amines and phenols can be
methylated. Methionine and cysteine act as methyl
donors.
• Examples: adrenaline, histamine, nicotinic acid.
• Ribonucleoside/nucleotide synthesis : activation of
many purine and pyrimidine antimetabolites used
in cancer chemotherapy
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, chlozepid
• 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, paracetamol
Acetylation: sulfonamides, isoniasid, novocainamid
Methylation: morphin, unitiol, ethionamid, noradrenalin
Metabolism in the intestinal wall
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 Biotransformation
Concurrent use of drugs: Induction and inhibition
• Genetic polymorphism
• Pollutant exposure from environment or industry
• Pathological status
• Age
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
character
Increasing of metabolism speed of certain drugs in case of diet with
dominance of proteins and carbohydrates
Decreasing of metabolism speed in case of heavy digestive disorders linked
with starvation (total or protein)
Environment
Alcohol
— one time
consumption
— chronic
consumption
Smoking
Way of
excretion
Increasing of metabolism speed if in contact
with chlorine insecticides
Depressing of enzymes that metabolise drugs
Induction of enzyme system
Increasing of metabolism of certain drugs (i.e.
theophyllin)
Metabolism in liver before entering system
circulation (first going-through effect) after
peroral administration of drugs
Circade changes in drugs metabolism
Time of
introduction of
drugs
Interaction of Stimulation
drugs
reaction
and
depression
of
enzyme
USING DRUGS DURING LACTATION
Absolutely contraindicated
• Antibacterial: tetracyclins, levomycetin, fluoroquinolones,
sulfonamides, nalidixic acid, metronidazole
• Antiviral: amantadin, gancyclovir, zidovudin, remantadin
• Cytostatics
• 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
USING DRUGS DURING LACTATION
(continuation)
Undesirable
Bromides, meprobamat, derivatives of benzodiazepine
(diazepam, chlozepid, oxazepam etc.), aminazin,
ethosuximid;
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 – quinidine
• Some enzyme inhibitors – Omeprazole,
metronidazole, isoniazide, ciprofloxacin and
sulfonamides
Microsomal Enzyme Induction
• 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 (NABQI)
• 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, that’s
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 it’s suitable to correct the dose according to
“ideal” body weight:
For men
ІBW = 50 + [(Н - 150) : 2,5]
For women
ІBW = 45 + [(Н - 150) : 2,5]
where Н – height in cm
• in case of normal body weight the dose is calculated
counting on 1 kg of patient’s body weight
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 Metabolism
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 bleeding—a 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 Metabolism
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 Metabolism
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
Presystemic elimination – extraction of the drug
from blood circulatory system during it’s 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, reserpin
Presystemic elimination
Clinical Relevance of Drug Metabolism
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
kidneys, liver, lungs,
intestines, sweat and mammary glands
etc.
through different ways:
Hydrophilic compounds can be easily excreted.
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)
ELIMINATION OF DRUGS (cont’d)
with bile – drugs and their metabolites with relative MM over 3000
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.
THANK YOU
-PHARMA STREET