Drug biotransformation (katzungs, Ch 4, trans 5) Flashcards
A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions. These reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (−OH, −NH 2, −SH).
Phase I
- *Often these metabolites are inactive, although in some instances activity is only modified or even enhanced
- *many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated functional group to form a highly polar conjugate. Such conjugation or synthetic reactions are the hallmarks of phase II metabolism
Many drug-metabolizing enzymes are located in the lipophilic endoplasmic reticulum membranes of liver and other tissues
Rough endoplasmic reticulum - protein synthesis
Smooth endoplasmic reticulum - rich in enzymes responsible for oxidative drug metabolism
REMEMBER Smooth endoplasmic reticulum contain class of enzymes known as the mixed function oxidases (MFOs) or monooxygenases
The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen
** 1 molecule is consumed (reduced) per substrate molecule; one oxygen atom appearing in the product and the other in the form of water
What is the rate-limiting step in hepatic drug oxidations
P450 heme reduction
Microsomal drug oxidations require P450, P450 reductase, NADPH, and molecular oxygen.
STEPS:
- oxidized (Fe 3+ ) P450 combines with a drug substrate to form a binary complex
- NADPH donates an electron to the flavoprotein P450 reductase, which in turn reduces the oxidized P450-drug complex
- A second electron is introduced from NADPH via the same P450 reductase, which serves to reduce molecular oxygen and to form an “activated oxygen”-P450-substrate complex
- This complex in turn transfers activated oxygen to the drug substrate to form the oxidized product
PHASE II reactions
Parent drugs or their phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates
In general, conjugates are polar molecules that are readily excreted and often inactive.
PHASE II reactions Glucuronidation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Glucuronidation
Endogenous Reactant: UDP glucuronic acid
Transferase (Location): UDP glucuronosyltransferase (microsomes)
Types of Substrates: Phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides
Examples: Nitrophenol, morphine, acetaminophen, diazepam, N-hydroxydapsone, sulfathiazole, meprobamate, digitoxin, digoxin
PHASE II reactions Acetylation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Acetylation
Endogenous Reactant: Acetyl-CoA
Transferase (Location): N–Acetyltransferase
(cytosol)
Types of Substrates: Amines
Examples: Sulfonamides, isoniazid, clonazepam, dapsone, mescaline
PHASE II reactions Glutathione conjugation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions Glutathione conjugation Endogenous Reactant: Glutathione (GSH) Transferase (Location): GSH-S-transferase (cytosol, microsomes) Types of Substrates: Epoxides, arene oxides, nitro groups, hydroxylamines Examples: Acetaminophen, ethacrynic acid, bromobenzene
PHASE II reactions Glycine conjugation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Glycine conjugation
Endogenous Reactant: Glycine
Transferase (Location): Acyl-CoA glycinetransferase (mitochondria)
Types of Substrates: Acyl-CoA derivatives of carboxylic acids
Examples: Salicylic acid, benzoic acid, nicotinic acid, cinnamic acid,
cholic acid, deoxycholic acid
PHASE II reactions Sulfation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Sulfation
Endogenous Reactant: Phosphoadenosyl phosphosulfate
Transferase (Location): Sulfotransferase (cytosol)
Types of Substrates: Phenols, alcohols, aromatic amines
Examples: Estrone, aniline, phenol, 3-hydroxycoumarin, acetaminophen, methyldopa
PHASE II reactions Methylation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Methylation
Endogenous Reactant: S-Adenosylmethionine
Transferase (Location): Transmethylases (cytosol)
Types of Substrates: Catecholamines, phenols, amines
Examples: Dopamine, epinephrine,
pyridine, histamine, thiouracil
PHASE II reactions Water conjugation Endogenous Reactant: Transferase (Location): Types of Substrates: Examples:
PHASE II reactions
Water conjugation
Endogenous Reactant: Water
Transferase (Location): Epoxide hydrolase (microsomes)
Types of Substrates: Arene oxides, cis-disubstituted
and monosubstituted oxiranes
Examples: Benzopyrene 7,8-epoxide, styrene 1,2-oxide, carbamazepine epoxide
REMEMBER
Biotransformation
- is the chemical transformation of the drug in the body into a metabolite
- the primary site of occurrence is the LIVER, however pre-systemic metabolism occurs in the GIT (presence of CYP450)
- it main purpose is to render the drug to be more water soluble allowing it to be excreted faster
- it does not always render the drug into its inactive form, rather it converts the drug to its active or inactive form
a. For better DISTRIBUTION, drugs must be unionized, lipid soluble, and non-polar
b. For better EXCRETION, drugs must be ionized, water soluble, and polar
c. Unionized form of WEAK ACID: PROTONATED form; WEAK BASE: NON-PRTONATED form
Metabolite – the byproduct of metabolism
Active
- capable of pharmacologic activity
- still reabosorbable
- less polar, less ionized, lipid soluble
Inactive
- more polar, more ionized, water soluble
DRUG METABOLIZING SYSTEMS
- Enzymes
- Non-enzymatic processes
- Rearrangement of UNSTABLE metabolites into STABLE complexes
ENZYMES
1. Substrate Specific Enzymes - can degrade the drug analogues of normal body substances
Ex: Acetylcholinesterase, Monoamine oxidase (MAO) and Catecholamine-o- methyl-transferase (COMT) degrade norepinephrine and other catecholamine
2. Broad Substrate Specific Enzymes - Degrade a broad spectrum of substances, does not degrade specific analogues of normal physiologic constituent
Ex: Broad Plasma Pseudocholinesterase degrades non-specific esters like succinylcholine (muscle relaxant) and procaine (ester-type anesthetic)
Non-enzymatic processes
Ex: hydrolysis (isoniazid)
LOCATION OF DRUG METABOLIZING ENZYMES
- LIVER – main site
- LUNGS, GIT (intestinal mucosa), SKIN, PLACENTA, KIDNEY – other tissues with enzymes
- SUBCELLULAR – endoplasmic reticulum, mitochondria, cytosol, lysosomes, nuclear envelope, plasma membrane
REMEMBER
- drug can undergo phase I then it is converted into a metabolite which inactive from there it could readily be excreted OR
- if the drug is active it has to pass through phase II making it polar, rendering it inactive, then excreted
HOWEVER, this is not always the case!
• a drug can undergo phase II first before phase I
• Isoniazid - anti TB drug; possesses a functional group that is actually acetylated in phase II and is hydrolyzed into nicotinic acid or your isonicotinic acid in phase I
PHASE 1 (NONSYNTHETIC)
- drugs are oxidized or reduced to a more polar form by introducing or unmasking a functional group (e.g., -OH, -COOH, -SH, -O-, or NH2)
- these moieties do little to increase the water solubility of the drug but usually lead to drug inactivation
- OXIDATIVE REACTIONS
- HYDROLYTIC REACTIONS
- REDUCTIVE REACTIONS
Phase I
Oxidative reaction
- utilizes microsomal cytochrome P450 monooxygenase and cytoplasmic enzymes
- most predominant (50% of drug interactions)
- occurs in ER and microsome
Paracetamol : N-oxidation
Ibuprofen: Hydroxylation
Important CYP450 Enzymes
CYP3A4: accounts for over 50% of drug metabolism in liver
CYP2D6: metabolizes opioid analgesics like codeine
CYP2C9: metabolizes warfarin and phenytoin
Phase I Hydrolytic reactions - involves ester and amide drug - compound broken in parts - intracellular (ER, cytoplasm) or extracellular (circulating in plasma)
Example of hydrolytic enzymes:
Procaine (ester): pseudocholinesterase;
Lidocaine (amide): liver microsomal cP450
Phase I Reductive reactions - involves azo, nitro, and carbonyl functional groups of drugs - hepatic nitroreductase - enzymes in cell cytoplasm
Dantrolene – nitro reduction in malignant hyperthermia
PHASE 2 (SYNTHETIC)
- drugs are conjugated with acetate, glucuronate, sulfate, or glycine
- most conjugated drug metabolites are inactive
CONJUGATION
- parent drug or metabolite coupled to endogenous substances
- acetyl CoA, glucuronic acid
- in ER and cytoplasm
- Clonazepam (acetylation); Isoniazid (acetylation)
- Glucuronidation is the most common conjugation reaction
EFFECTS OF DRUG METABOLISM
Increased polarity (increased renal elimination)
- highly polar drugs are poorly absorbed, poorly transported across membranes, readily excreted
- the higher the lipid solubility and lower polarity, the higher the half-life of the drug
clinical correlation
Question: If the drug is highly lipid soluble and highly localized, usually the estimated half life is 100 days but you cannot give the drug every 100 days because you need to maintain a steady state plasma concentration. What will you do?
Answer: You should increase the dose (double the dose). For example, you are administering a 500mg drug, give a loading dose, you double the dosage, make it 1000mg. After which, you give maintenance doses
EFFECTS OF DRUG METABOLISM
Increased Water Solubility (increased renal elimination)
- increases in polarity of drug and water solubility
- addition of N, S, O, halogen
- rendered more polar – rapidly excreted
- *metabolism does not always result in increase water solubility
e. g. Procainamide => N-acetylprocainamide (NAPA is more active, longer half-life)
EFFECTS OF DRUG METABOLISM
Increase Degree of Ionization (increased renal elimination)
- many metabolites are more acidic than parent dugs, more ionized physiologic pH (7.4)
- acidic compounds excreted as anions in renal tubules are more ionized, hence rapidly eliminated
EFFECTS OF DRUG METABOLISM
alter pharmacologic activity (active to inactive metabolites)
- excreted out of the system
e. g. Erythromycin (macrolide): antibiotic, treatment of infection
EFFECTS OF DRUG METABOLISM
alter pharmacologic activity (active to active)
Phenacetin => Paracetamol/acetaminophen (toxic nephritis)
Diazepam => Desmethyldiazepam, Oxazepam (valium – anti anxiety)
Codeine => Morphine
Caffeine => Theophylline (bronchodilator, must be monitored closely due to low therapeutic index)
EFFECTS OF DRUG METABOLISM
alter pharmacologic activity (prodrug to active drug)
- prodrugs are inactive precursors without pharmacologic activity
Chloral hydrate => Trichloroethanol (sedative hypnotic)
Prednisone => Prednisolone
Cortisone => Hydrocortisone
Sulindac => Sulindac sulfide (NSAID)
EFFECTS OF DRUG METABOLISM
alter pharmacologic activity (Active Drug to Toxic Metabolites)
- EPOXIDES
- HYDROXYLAMINES - oxidized derivative of ammonia
- ACTIVATED OXYGEN (SUPEROXIDES)
4 FREE RADICALS
Epoxides - these are highly reactive chemical intermediates that form covalent bonds with nucleophilic functional groups of biologic macromolecules, nucleic acids, or proteins causing carcinogenesis, teratogenicity, and tissue damage
e.g.
1. Paracetamol => N-acetyl-p-benzoquinone imine (toxic metabolite formed if Paracetamol is taken in excess)
• 95% of paracetamol undergoes glucuronidation, 5% goes to a pathway called cytochrome p450 dependent, your glutathione conjugation
• If a a person is already deficient of your glutathione then there is a production of this toxic metabolite and can cause hepatotoxicity
• Antidote: N-acetylcysteine to be given right away, between 8-16 hours
2. Isoniazid (INH), an anti TB drug whose toxic metabolite is acetylhydrazine
• hepatotoxic; only given once a day as prophylaxis to patients exposed to TB
REMEMBER
Very young: Decreased Metabolism
- Metabolic sites not yet fully developed, hence less enzyme synthesis
Ex. Chloramphenicol-in babies, there is little glucuronyl transferase to degrade the drug which makes it toxic, leading to “Gray baby syndrome” (Manifestations: Cyanosis, nausea and vomiting, leading to circulatory collapse and progress to death. NEVER give it to children less than 3 years old.)
Very old: Decreased Metabolism
- Due to the wear and tear of tissues, there is decrease tissue activity, decreased enzymatic activity.
- When you prescribe medicine to the elderly, you usually give half the dose.
Enzyme inducers increases drug metabolism
**decreased drug effect
Enzyme inhibitors decreases drug metabolism
**increase drug effect
Enzyme inducers: Drug whose metabolism is enhanced
Benzo[a]pyrene: Theophylline
Chlorcyclizine: Steroid hormones
Ethchlorvynol: Warfarin
Glutethimide: Antipyrine, glutethimide, warfarin
Griseofulvin: Warfarin
Phenobarbital and other barbiturates (except secobarbital): Barbiturates, choramphenicol, cortisol, coumarin anticoagulants, desmethylimipramine, digitoxin, doxorubicin, estradiol, phenylbutazone, phenytoin, quinine, testosterone
Phenylbutazone: Aminopyrine, cortisol, digitoxin
Phenytoin: Cortisol, dexamethasone, digitoxin, theophylline
Rifampicin: Coumarin anticoagulants, digitoxin, glucocorticoids, methadone, metoproplol, oral contraceptives, predinisone, propanolol, quinidine
Phenobarbital: Phenytoin (anti-epileptic)
Enzyme inhibitors: Drug whose metabolism is decreased
Cimetidine: Warfarin (Oral anticoagulant)
Erythromycin: Theophylline (bronchodilator)
Terfenadine; Ketoconazole (anti-fungal)
First order kinetics:
- linear, non-saturable
- a constant fraction or percentage of a drug is handled per unit time
- rate of process is directly proportional to the concentration of the substance remaining to be handled by the system at any given time
- drug concentration does not saturate the enzyme or carrier system, hence, double the dose, double the concentration
zero order kinetics:
- non-linear, saturable
- a constant amount of drug is handled per unit time
- the rate process becomes independent of the drug concentration and dependent on only the rate constant, k, of the process
- drug concentration may saturate the metabolic and transport systems (e.g. facilitated diffusion, active transport, biotransformation reactions)
- Michaelis Menten Kinetics is an example of this
- increasing the doses to high levels increases the free form level of the drug due to the saturation of the enzymes that degrade it
five drugs that were well studied following zero order kinetics:
- ASPIRIN (acetyl salicylic acid)
- PHENYTOIN (anticonvulsant)
- ETHANOL
- DICOUMAROL (oral anticoagulant)
- PROBENECID (uricosuric drug)
Clearance, CL = rate of elimination/plasma concentration
- Clearance may vary per organ (kidney, lung, skin), thus, total systemic clearance is additive it is additive
2 major organs of elimination: KIDNEY and LIVER. Most important clearance is the renal clearance because most are excreted/eliminated through the kidneys, thus it will dictate the rate of elimination of the drugs from the body.
HALF-LIFE, t1/2
- it is the time required for the plasma concentration in the body to fall by 50%
- it is applicable only to FIRST ORDER KINETICS
- it is a function of the volume of distribution and clearance
t1/2 = 0.693 Vd / Cl
HIGHEST plasma concentration reached after each dose
Peak level
LOWEST plasma concentration reached between dosing intervals
Trough or valley level
- best time to get blood samples
when an EQUILIBRIUM has been reached between dose of drug and the amount being eliminated
Steady state plasma concentration level
**achieved after 4 HALF-LIVES (wait for 4 half-lives before drawing blood)
dose intended to achieve steady-state level within the optimal therapeutic range
Maintenance Dose = Dosing rate x Dosing interval
LOADING DOSE
- may be a single dose or a series of doses to achieve target concentration rapidly
- used when trying to reach therapeutic level without waiting for four half-lives
- for most drugs, LD can be given as a single dose by the chosen route of administration
- depends upon the elimination half-life, dosing interval, and the therapeutic (target) concentration
- followed by a maintenance dose
Loading Dose = Volume of Distribution x Target Concentration
describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose (therapeutic
threshold)
THERAPEUTIC RANGE or THERAPEUTIC WINDOW
- ABOVE the therapeutic threshold => TOXICITY
- BELOW the therapeutic threshold => NO CLINICAL EFFECT
- the LARGER the RANGE, the SAFER the DRUG
ratio of the TD50 (or LD50) to the ED50
Therapeutic index
LD50 – Median Lethal Dose
TD50 – Median Toxic Dose
ED50 – Median Effective Dose that produces a response at 50% of the population
What are the indications for monitoring drug levels?
- drug has a narrow therapeutic index
- To evaluate dose-related toxicity
- To evaluate therapeutic inefficacy
- To guide dose selection in prophylactic treatment
- To guide dose adjustment based on pharmacokinetic principles
- There are possible drug-drug interactions
- Loading dose regimen is being used
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP1A2 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP1A2
Substrates: Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tacrine, tamoxifen, theophylline, warfarin
Inducer: Smoking, charcoal-broiled foods, cruciferous vegetables, omeprazole
Inhibitor: Galangin, furafylline, fluvoxamine
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2A6 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2A6
Substrates: Coumarin, tobacco nitrosamines, nicotine
Inducer: Rifampin, phenobarbital
Inhibitor: Tranylcypromine, menthofuran, methoxsalen
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2E1 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2E1
Substrates: Acetaminophen, chlorzoxazone, enflurane, halothane, ethanol (a minor pathway)
Inducer: Ethanol, isoniazid
Inhibitor: 4-Methylpyrazole, disulfiram
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2B6 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2B6
Substrates: Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine, S-mephobarbital, S-mephenytoin (N-demethylation to nirvanol), methadone, nevirapine, propofol, selegiline, sertraline, ticlopidine
Inducer: Phenobarbital, cyclophosphamide
Inhibitor: Ticlopidine, clopidogrel
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2C8 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2C8
Substrates: Taxol, all-trans-retinoic acid
Inducer: Rifampin, barbiturates
Inhibitor: Trimethoprim
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2C9 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2C9
Substrates: Celecoxib, flurbiprofen, hexobarbital, ibuprofen, losartan, phenytoin, tolbutamide, trimethadione, sulfaphenazole, S-warfarin, ticrynafen
Inducer: Barbiturates, rifampin
Inhibitor: Tienilic acid, sulfaphenazole
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2C18 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2C18 Substrates: Tolbutamide, phenytoin Inducer: Phenobarbital Inhibitor: -
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2C19 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2C19
Substrates: Diazepam, S-mephenytoin, naproxen, nirvanol, omeprazole, propranolol
Inducer: Barbiturates, rifampin
Inhibitor: N3-benzylnirvanol, N3-benzylphenobarbital, fluconazole
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP2D6 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP2D6
Substrates: Bufuralol, bupranolol, clomipramine, clozapine, codeine, debrisoquin, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, haloperidol, hydrocodone
Inducer: -
Inhibitor: Quinidine, paroxetine
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors. CYP3A4 Substrates: Inducer: Inhibitor:
Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and selective inhibitors.
CYP3A4 (CYP3A5 has similar substrate and inhibitor profiles, but except for a few drugs is generally less active than CYP3A4.)
Substrates: Acetaminophen, alfentanil, amiodarone, astemizole, cisapride etc
Inducer: Barbiturates, carbamazepine, glucocorticoids,
Inhibitor: Azamulin, clarithromycin, diltiazem, erythromycin, fluconazole
Enzyme inducer:
Environmental chemicals and pollutants are also capable of inducing P450 enzymes. As previously noted, exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons, which are present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce CYP1A enzymes and to alter the rates of drug metabolism
Increased P450 synthesis requires enhanced transcription and translation along with increased synthesis of heme, its prosthetic cofactor. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[ a ]pyrene, dioxin) has been identified. The translocation of the inducer-receptor complex into the nucleus, followed by ligand-induced dimerization with Arnt, a closely related nuclear protein, leads to subsequent activation of regulatory elements of CYP1A genes, resulting in their induction
Enzyme inducer: A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3A induction by various chemicals (dexamethasone, rifampin, mifepristone, phenobarbital, atorvastatin, and hyperforin, a constituent of St. John’s wort) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR), has been identified for the relatively large and structurally diverse phenobarbital class of inducers of CYP2B6, CYP2C9, and CYP3A4. Peroxisome proliferator receptor α (PPAR-α) is yet another nuclear receptor highly expressed in liver and kidneys, which uses lipid-lowering drugs (eg, fenofibrate and gemfibrozil) as ligands.
Consistent with its major role in the regulation of fatty
acid metabolism, PPAR-α mediates the induction of CYP4A enzymes, responsible for the metabolism of fatty acids such as arachidonic acid and its physiologically relevant derivatives. It is noteworthy that on binding of its particular ligand, PXR, CAR, and PPAR-α each form heterodimers with another nuclear receptor, the retinoid X-receptor (RXR). This heterodimer in turn binds to response elements within the promoter regions of specific P450 genes to induce gene expression.
Enzyme inhibitor:
Certain drug substrates inhibit cytochrome P450 enzyme activity. Imidazole-containing drugs such as cimetidine and ketoconazole bind tightly to the P450 heme iron and effectively reduce the metabolism of endogenous substrates (eg, testosterone) or other co-administered drugs through competitive inhibition.
Macrolide antibiotics such as troleandomycin, erythromycin, and erythromycin derivatives are metabolized, apparently by CYP3A, to metabolites that complex the cytochrome P450 heme iron and
render it catalytically inactive. Another compound that acts through this mechanism is the inhibitor proadifen (SKF-525-A, used in research), which binds tightly to the heme iron and quasiirreversibly inactivates the enzyme, thereby inhibiting the metabolism of potential substrates.
