Drug Metabolism

The liver is the capital of drug metabolism. Although the metabolism inactivates drugs generally, some drug metabolites are pharmacologically active – sometimes even more than the starting material. An inactive or weakly active substance which has an active metabolite (prodrug) called prodrug, especially if it was designed to provide the active part of effective available.

(See also Overview pharmacokinetics.) The liver is the main town in the drug metabolism. Although the metabolism inactivates drugs generally, some drug metabolites are pharmacologically active – sometimes even more than the starting material. An inactive or weakly active substance which has an active metabolite (prodrug) called prodrug, especially if it was designed to provide the active part of effective available. Which process always occurs, the aim is to facilitate the excretion of the drug. The metabolism of drugs can be effected by oxidation, reduction, hydrolysis, hydration, conjugation, condensation or isomerization. The enzymes involved in the metabolism are present in many tissues, but generally in the liver more concentrated. The rate of drug metabolism varies greatly between patients. In others, the metabolism can take place so slowly that the usual doses have toxic effects. In some patients the metabolism of the drug is so fast that the therapeutically effective blood and tissue concentrations are not reached. The individual rates of drug metabolism by genetic factors, comorbidities (particularly chronic liver disease and advanced heart failure) as well as drug interactions influenced (especially those who are involved in induction or inhibition of metabolism). In many drug metabolism occurs in two phases. Phase I reactions include the formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis). These reactions are non-synthetic. Phase II reactions involve conjugation with an endogenous substance (eg. B. glucuronic acid, sulfate, glycine). These reactions are synthetic. The metabolites formed in synthetic reactions are more polar and therefore be more easily via the kidneys (in urine) and the liver (in bile) excreted as those which are formed in non-synthetic reactions. Some medicines are subject only to Phase I or Phase II reactions. Thus, the number of phases reflect rather reflected a functional as a sequential classification. Rate Virtually all drugs, the rate of metabolism for all existing pathways has an upper limit (capacity limit). At therapeutic concentrations of most drugs, however, only a small fraction of the binding sites occupied, and the metabolic rate increases with the concentration of the drug. In such cases, as the elimination (kinetics) of the first order are referred to, the rate of metabolism of the drug is a constant proportion of the drug that remains in the body (i. E., A drug has a specific half-life). If z. B. null 500 mg in the body are present at the time, can be prepared by metabolism 250 mg after 1 hour and 125 mg after 2 h be present (which is the half-life of 1 hour illustrated). However, if most of enzyme binding sites are occupied, the metabolism occurs with maximum rate and changes not related to the drug concentration. Instead, a fixed amount of drug per unit time is metabolized (zero-order kinetics). When 500 mg are present in this case in the body at time zero, can be prepared by metabolism 450 mg after 1 hour and 400 mg after 2 h be present (which gives a maximum clearance of 50 mg / h and no specific half-life illustrated). When the concentration of the drug increases, the metabolism shifts from a first to a zero-order kinetics. Cytochrome P-450 is the most important enzyme system of the phase I metabolism cytochrome P-450 (CYP 450), a microsomal superfamily of isoenzymes which catalyzes the oxidation of numerous drugs. The electrons are provided by the NADPH-CYP450 reductase, a flavoprotein that electrons from NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) transmits to CYP450. CYP450-enzymes can be induced by numerous drugs and substances or inhibited, which leads to drug-drug interactions, in which a drug enhances the toxicity of a drug or other reduces its therapeutic effect. Examples of drugs that interact with specific enzymes, see table: Known substances that interact with the cytochrome P-450 enzyme system interacts and some drugs with potentially serious drug-drug interactions *. Known substances which interact with the cytochrome P-450 enzyme system enzyme substrates inhibitors Inducing substances CYP1A2 paracetamol caffeine clarithromycin estradiol, haloperidol, lidocaine, methadone olanzapine propranolol ritonavir tacrine theophylline Tricyclic antidepressants verapamil (R) warfarin amiodarone cimetidine, ciprofloxacin, erythromycin fluvoxamine ticlopidine over charcoal grilled beef cigarette smoke omeprazole phenobarbital phenytoin rifampin CYP2C9 celecoxib diclofenac fluoxetine glipizide glyburide, indomethacin, nifedipine phenytoin piroxicam progesterone testosterone Tricyclic antidepressants valproate voriconazole (S) warfarin cimetidine, amiodarone, fluconazole lovastatin ritonavir sertraline sulfamethoxazole trimethoprim topiramate voriconazole, zafirlukast dexamethasone, phenobarbital, phenytoin, barbiturates Other rifampicin CYP2C19 diazepam (S) -mephenytoin omeprazole pentamidine propranolol voriconazole ( R) warfarin cimetidine, fluoxetine, fluvoxamine, ketoconazole lansoprazole, omeprazole, paroxetine Ticlopidine carbamazepine phenobarbital prednisone rifampicin CYP2D6 beta blockers codeine dextromethorphan flecainide haloperidol lidocaine mexiletine morphine omeprazole phenothiazines quinidine risperidone SSRI tamoxifen testosterone tramadol Trazodone Tricyclic antidepressants venlafaxine amiodarone bupropion celecoxib cimetidine fluoxetine fluvoxamine metoclopramide methadone paroxetine quinidine ritonavir sertraline carbamazepine dexamethasone, phenobarbital, phenytoin rifampin CYP2E1 acetaminophen alcohol D isulfiram alcohol isoniazid tobacco CYP3A4 amiodarone aprepitant azole antifungals benzodiazepine calcium channel blocker caffeine carbamazepine clarithromycin cyclosporin delavirdine Enalapril estradiol estrogen erythromycin, fentanyl, finasteride indinavir lidocaine lopinavir loratidine methadone nelfinavir omeprazole opioid analgesics prednisone progesterone ritonavir saquinavir Sildenafil sirolimus statins, tacrolimus, tamoxifen Tricyclic antidepressants (R) warfarin amiodarone atazanavir azole antifungal agents cimetidine, ciprofloxacin, clarithromycin delavirdine diltiazem, erythromycin, fluoxetine, fluvoxamine grapefruit juice indinavir metronidazole Nef azodon nelfinavir, nifedipine, omeprazole, paroxetine posaconazole propoxyphene ritonavir, saquinavir, sertraline verapamil voriconazole carbamazepine dexamethasone isoniazid phenobarbital, phenytoin, prednisone rifampicin When aging, the capacity of the liver decreases with respect to the metabolism by the CYP450 enzyme system to ? 30%, because reduce the haptic volume and the blood flow rate. Therefore reach among older drugs that are metabolized by this system, higher levels and have extended half-lives (comparison of pharmacokinetic results for diazepam in a younger (A) and an older man (B).). Since the hepatic microsomal enzyme systems are partially developed in newborns, they also have problems with the metabolism of many drugs. Glucuronidation conjugation, the most common phase II reaction, is the only that takes place in the microsomal enzyme system of the liver. Glucuronide secreted in bile and excreted in the urine. Therefore, conjugation increases the solubility of most drugs and facilitates their excretion via the kidneys. A Aminosäurekonjugation with glutamine or glycine results in conjugates that are easily excreted in the urine, but given only to a small extent in the bile. Aging does not affect the glucuronidation. However, in newborns the conversion to the glucuronide is slower, possibly with serious consequences (eg. As in chloramphenicol). Conjugations can also be made as acetylation or Sulfokonjugationen. Sulfatester are polar and are easily excreted in the urine. Getting older does not influence these effects.

Health Life Media Team

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