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
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Elimination of the drugs
Metabolism orbiotransformation -
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 )
N-oxypropranololBiotransformation of drugs into active (or more active) metabolites
І phase (nonsynthetic reactions):
(oxydation, reduction, hydrolysis)
Reactions of І phase - transformation in molecule with formation of functional groups with active hydrogen atom
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 substancesThe catalytic cycle of cytochrome P450
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 О2is 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
Synthetic and nonsynthetic reactions take place
Concurrent use of drugs: Induction and inhibition
For menІBW = 50 + [(Н - 150) : 2,5]
For women ІBW = 45 + [(Н - 150) : 2,5]
where Н – height in cm
Many substrates are retained not only at the activesite of the enzyme but remain nonspecifically bound to the lipid membrane of the endoplasmicreticulum. In this state, they may induce microsomal enzymes; depending on the residual druglevels at the active site, they also may competitively inhibit metabolism of a simultaneously
Enzyme-inducing drugs include various sedative-hypnotics, tranquilizers, anticonvulsants, andinsecticides. Patients who routinely ingest barbiturates, other sedative-hypnotics, ortranquilizers may require considerably higher doses of warfarin (an oral anticoagulant) to maintaina prolonged prothrombin time. On the other hand, discontinuance of the sedative may result inreduced 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 receivingvarious combination drug regimens such as antipsychotics or sedatives with contraceptive agents,sedatives with anticonvulsant drugs, and even alcohol with hypoglycemic drugs (tolbutamide).
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 narrowtherapeutic indices.
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 inpatients receiving allopurinol. Cimetidine, a drug used in the treatment of peptic ulcer, has beenshown to potentiate the pharmacologic actions of anticoagulants and sedatives. The metabolism ofthe 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 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
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
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 excreted.
filtration,canalicular secretion and
if 90-300 – with urine and bile):ampicillin, gentamicin, urosulfan, novokainamid, digoxin
lipid-solubledrugs are reabsorbedpassively
ionizeddrugs, 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)
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 volatilesubstances: ether for narcosis, ftorotan, N2O, partly – camphor, iodides, ethanol
through intestine:ftalasol, enteroseptol, magnesium sulfate
throughsweat glands:iodides, bromides, salicylates
through bronchial, salivary glands:bromides, iodides
withmilk:get into organism of the baby – levomycetin, fenilin, reserpin, lithium remedies, meprotan, tetracyclines, sulfonamides etc.