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unionized non-charged molecule first-order absorption process who's rate is determined by concentration of the drug at the absorption site?
analytical method used to determine if protein synthesis has been up-regulated or down-regulated in response to exposure to a drug by determining or measuring gene expression?
DNA gene chip microarray
excretion of a molecule that has been conjugated with a water soluble modifier such as glucuronic acid into the bile followed by colonic bacterial glucuronidase processing and then reabsorption into the systemic circulation?
alternate physical forms of a drug product that have different solubilities and properties that can alter bioavailability?
a method of measurement of the lipid solubility of a drug molecule?
n-octanol/water partition coefficient
common method measuring levels of serum creatinine that determines the ability of the renal system to filter and eliminate exogenous or endogenous substances?
metabolic processing of a drug molecule rapidly following oral absorption of a drug molecule and its distribution via the portal vein into the liver?
first pass effect
pH at which a molecule exists as 50% ionized and 50% unionized?
a hydrophobic and/or ion-exchange interaction that produces a reservoir of a drug molecule unavailable for drug-receptor interactions and metabolism- one cause of serious drug interactions?
plasma protein binding
delivery method that can avoid first-pass metabolism?
sublingual or buccal
molecules with 2 or more optically active chiral centers are present and each one has different physical properties?
drug delivery system that utilizes blood brain barrier amino acid transport to get the drug into the brain followed by decarboxylase processing to produce dopamine-always used in conjunction with carbidopa?
binding of an agonist or antagonist NOT to the receptor site but distant from it leading to alteration in activity?
the study of the science of how do genes affect the way that individuals respond to drug exposure?
the study of how drugs interact with receptors on proteins and cells that leads to a particular response?
structural components or functional groups of a molecule whose steric, electronic, and solubility characteristics are interchangeable?
double ester/carbonate approach used to create an acceptable esterase substrate for penicillins and cephalosporins e.g. Vantin?
prodrug ester for beta-lactams
NSAID which is a bioprecursor that requires oxidative decarboxylation to create the active COX inhibitor?
a molecule that decreases or prevents a desired or natural response known as intrinsic activity?
water soluble injectable antibacterial prodrug ester designed to prevent painful injection?
a carbacephalosporin antibacterial agent that contains methylene isosteric replacement of the normal sulfur atom in Cefaclor/Ceclor?
azo linkage prodrug which uses colonic bacterial reductase to deliver an antibiotic and anti-inflammatory agent selectively to the lumen of the colon with minimal systemic absorption?
molecules in which all physical properties are identical except for the direction they rotate plane polarized light?
an anticoagulant drug that demonstrates variable pharmacogenomic properties due to individual patient variability in the metabolic CYP2C9 enzyme and the Vitamin K reductase target called VKORC1?
anti-viral ophthalmic agent that requires phosphorylation for activity?
increase or upregulation of a metabolic process usually in response to a stimuli cuased by another drug or environmental chemicals- an actual increase in the number of enzyme molecules via biosynthesis?
drug used long term for prophylaxis/elimination of frequent UTI; selectively releases formaldehyde in the urine due to the local acidic pH?
the study of how drugs are processed by the body (metabolism and elimination)?
macrolide antibacterial agent used in upper/lower respiratory infections such as Legionnaire's disease?
a molecule that initiates a desired or natural response known as intrinsic activity?
Which two drugs undergo oxidation at allylic carbons?
- 1. Pentazocine (Talwin)
- --used for pain and pre/post op
- 2.Quinidine (Quinidex, Quinalan, Quinaglute, Cardioquin)
Which two drugs undergo oxidation at the alpha carbon located next to carbonyls and amines?
- 1. Diazepam (Valium, Diastat is rectal form)
- --anticonvulsant if patient is having N/V
- --antianxiety, skeletal muscle relaxant
- *gets converted to Oxazepam (Serax) metabolite, which is now marketed (alcoholic detox)
- 2. Glutethimide (C2)
- --3-7 days for insomnia
What is an imine?
a carbon double bonded to a nitrogen (C=N)
Where does oxidation at aliphatic and alicyclic carbons happen?
- in drugs with straight or branched alkyl chains
- at terminal methyl groups (omega position)
- at the next to last carbon (omega 1 position)
- initially it inserts a hydroxyl group but oxidation can continue to afford aldehydes, ketones, or carboxylic acid groups
- also occurs in saturated alkyl rings like cyclohexyl rings
Induction and Inhibition: Which is immediate and which can take up to a week?
- induction= week
- inhibition= immediate
What are two drugs that undergo oxidation at aliphatic carbons?
- 1. Chlorpropamide (Diabinese)
- --oral anti-diabetic sulfonylurea
- 2. Ibuprofen (Advil, Motrin, Genpril, Haltran, Menadol, Nuprin)
What are two drugs that undergo oxidation at an alicyclic carbon?
- 1. Acetohexamide (Dymelor)
- --oral antidiabetic sulfonylurea
- 2. Minoxidil (Lonetin and Rogaine)
- --Lonetin=severe unresponsive hypertension
- --Rogaine=male pattern baldness
What does oxidation involving carbon-heteroatom systems mean?
- it is oxidation of the carbon attached to either oxygen, sulfur or nitrogen
- aka N-dealkylation, O-dealkylation, or S-dealkylation reactions!
____ ______ are NADPH-dependent flavoproteins that require oxygen, but they do NOT contain ferric ion-heme centers?
amine oxidases (N-oxidases)
What are four drugs that undergo tertiary aliphatic and alicyclic amines?
- 1. Lidocaine (Xylocaine)
- --ventricular arrythmias, herpes neuralgia, local anesthetic
- 2. Chlorpromazine HCl (Thorazine)/Phenothiazine
- --antiemetic, antivertigo, antipsychotic
- --neurotoxic= thorazine shuffle in nursing home
- 3. Tamoxifen citrate (Nolvadex)
- --#1 drug for breast cancer, antiestrogen hormone, gynecomastia
- 4. Nicotine (Habitrol, Prostep, Nicorette, Nicotrol, Nicoderm)
___ amines are subject to N-dealkylation, oxidative deamination, and N-oxidations
N-dealkylation proceeds similar to tertiary amines by what pathway?
What are two drugs that undergo oxidation by a secondary or primary amine?
- 1. Propranolol HCl (Inderal)
- --nonselective beta-adrenergic blocker
- --used for test anxiety, stage fright
- 2. Methylphenidate (Ritalin)
- --ADHD and narcolepsy
If a secondary amine contains a methyl or other appropriate group then _____ formation is possible?
What are two drugs that undergo oxidation by a primary amine at the tertiary carbon?
- 1. Phentermine HCl (Ionamin, Adipex-P, Zantryl, Fastin)
- --managing obesity, appetite suppressant, used to study)
- 2. (dl) Amphetamine sulfate
- -- ADHD, narcolepsy
- --an imine, an oxine, and phenylacetone formed
- *phenylacetone can be found in the urine of meth users
N-hydroxy compounds are stable or unstable?
- chemically unstable
- hydroxylamine to nitroso to nitro is unstable, carcinogenic, and will undergo further oxidation
What two reactions are relatively rare in drugs because of their toxicity?
- oxidation of tertiary aromatic amines
- oxidation of secondary aromatic amines
What is a drug that undergoes oxidation of a nitrogen heterocycle?
- Trimethoprim-Dihydrofolate reductase inhibitor (Trimpex, Proloprim, in combo form Bactrim, Septra, Cotrim
- --antibiotic treating UTIs, HIV pneumonia
*another example is nicotine to cotinine (which is found in the urine of smokers)
What are two examples of drugs that undergo oxidation of an amide?
- 1. Diazepam -->Desmethyldiazepam
- 2. Cyclophosphamide (Cytoxan, Neosar)
- --anticancer drug
- --must undergo oxidation to become the active form of the drug, phosphoramide mustard
- *Note: a dangerous metabolite from this rxn is acrolein, which can cause hemorrhagic cystitis
What is a drug that undergoes oxidation by a carbon-oxygen system?
- codeine (tylenol #3) ---> morphine
- *some people do not have pain relief from codeine b/c they cannot metabolize/slow metabolize it to the morphine form
What are some drugs that O-dealkylate?
T/F: S-dealkylations occur often.
false; b/c there are not many sulfur containing drugs and competing S-oxidations
Desulfurizations involve C=S conversion to ?
What is a drug that undergoes desulfurization?
- Thiopental (Pentathol)
- --induces anesthesia to get you through stage 1 of anesthesia where you would puke
- --converts to Pentobarbitol
What is a drug that undergoes sulfur oxidation?
- Thioridazine (Mellaril)
- --antipsychotic tranquilizer
- --converts to Mesoridazine (Serentil) which is also a good antipsychotic and is not as toxic as parent drug
What phase 1 reaction is catalyzed by alcohol dehydrogenase in the liver and other tissues and may also need NADP+ as a cofactor?
oxidation of alcohols and aldehydes
What is a drug that undergoes oxidative dehalogenation?
- Halothane (Fluothane)
- --general anesthetic, not used much anymore b/c causes extreme liver damage from the HCl acid metabolite that is formed
What is a drug that undergoes oxidative aromatization or dehydrogenation?
- --a progestin that is in a lot of oral contraceptives
- --aromatase converts it to an estrogen
___ plays a role in conversion of azo, carbonyl, and nitro groups?
reduction (phase 1)
____ reductions generate alcohols, while _____ and _____ reductions generate amines?
- nitro and azo= amines
What enzymes mediate the reductive reactions?
Aldo-Keto reductase enzymes
Where are Aldo-Keto reductase enzymes found?
- liver and kidney
- they use NADPH as their source of H-
Bioreduction of _____ is often stereospecific or stereoselective for one isomer over the other?
What is a drug that is a stereoselective reduction of a ketone?
R+ Warfarin--> 90% major diastereomer and 10% minor diastereomer
_____ ____ play a role in the enterohepatic recirculation of nitro or azo containing drugs?
What are two drugs that undergo reduction of a nitro or an azo compound?
- 1. Dantrolene (Dantrium)
- --direct acting skeletal muscle relaxant to avoid muscles cooking
- --used in spasticity, malignant hyperthermia
- 2. Sulfasalazine (Azulfidine)
- --sulfonimide antiobiotic and anti-inflammatory used to treat ulcerative colitis, rheumatoid arthritis
- --antibiotic= sulfapyridine metab
- --anti-inflammatory= 5-aminosalicylic acid metab
What are two drugs that undergo miscellaneous reductions (rare)?
- 1. Disulfiram (Antabuse)
- --treats chronic alcoholism
- 2. Sulindac (Clinoril)
- --NSAID, prodrug --->active thiol
What are three drugs that undergo hydrolysis of an ester or an amide (phase 1)?
- 1. Aspirin
- 2. Clofibrate (Atromid-S)
- 3. Prazosin (Minipress)
- --antihypertensive alpha-1 adrenergic blocker
T/F: Amides are harder to hydrolyze than esters because they are more stable in our bodies.
What are the easiest molecules to hydrolyze?
T/F: many prodrugs are esters.
What are some new biotech drugs that are esters?
- human insulin
- growth hormone
What are some of the miscellaneous hydrolytic reactions?
- beta glucuronidases hydrolyze sugars from cardiac glycosides
- epoxide hydrases
What is the most common conjugation pathway (phase 2)?
Which enzyme mediates the glucuronidation process?
- UDP-glucuronyl transferase
- found in liver, intestine, brain, kidney, lung
T/F: glucuronidation is a stereospecific process.
true; the beta position
T/F: diglucuronic acid conjugates are very rare.
Where do oxygen glucuronides attach? What are the 2 most common?
- *phenol hydroxyls
- carboxylic acid hydroxyls
What is a drug that undergoes oxygen glucuronidation onto an enol?
What is a drug that undergoes oxygen glucuronidation on an alcohol?
- Chloramphenicol (Chloromycetin)
- --serious infections
- --monitor for blood dyscrasias
What is a drug that undergoes oxygen glucuronidation on a phenol?
What is a drug that undergoes oxygen glucuronidation on a carboxylate?
- Fenoprofen (Nalfon)
What is a drug that undergoes oxygen glucuronidation on an N-hydroxyl?
- --treats leprosy, brown recluse bites, pcp in HIV
What enzymes catalyze sulfate conjugations?
- sulfotransferases in liver, kidney and intestine
- limited supply in body
Which type of conjugation (phase 2) occurs primarily with phenols and rarely with alcohols, aromatic amines, and N-hydroxyl compounds?
Which conjugation usually leads to inactive water-soluble metabolites?
What are two drugs that undergo sulfate conjugation?
- 1. Alpha-Methyldopa (Aldomet)
- 2. Albuterol (Proventil, Ventolin, Airet)
- --sympathomimetic bronchodilator
- --treats bronchospasms in COPD, asthma
What 2 amino acids are used to conjugate in humans?
What is a drug that is conjugated with glycine?
- Isoniazid (Laniazid, Nydrazid)
- --anti TB
- -->isonicotinic acid------>reacted by ATP and Coenzyme A-----> creates a glycine conjugate to be excreted
Which pathway allows chemically reactive electrophilic chemicals to be detoxified?
Glutathione conjugation (GSH)
Why are reactive electrophillic chemicals so bad? (why do we need GSH conjugation)
- they are toxic by:
- tissue necrosis
What acts as a sponge to scavenge any potent electrophiles that might cause damage?
thiol (SH) group in GSH conjugation
T/F: GSH conjugates are excreted.
false; undergo further metabolism
Which enzyme mediates GSH conj?
- glutathione s-transferase
- highly nucleophillic thiol sulfur so doesn't need a preactivated species
What are two drugs that undergo GSH conjugation by nucleophillic displacement?
- 1. Nitroglycerin
- --nitrate vasodilator for treating angina
- 2. Azathioprine (Imuran)
- --immunosuppressant used to treat transplantation and rheumatoid arthritis
What is a Michael addition?
- nucleophile adding to an alpha,beta-unsaturated carbonyl compound
- --GSH conj
Which conjugation is important for detoxifying arene oxides (epoxides)?
What are two drugs that undergo GSH Michael Addition conjugation?
- 1. Ethacrynic Acid (Edecrin)
- --loop diuretic used to decrease edema from CHF or renal and hepatic disease
- --=lots of urine!
- 2. APAP
- ---APAP oxidized to Iminoquinone which will cause liver failure if you run out of GSH reserves *so do not take APAP while drinking alcohol or for hangover (liver failure)
What sometimes prevents a Michael addition to the double bond in a GSH conjugation?
What two conjugation processes do NOT increase water solubility?
Acetylation (Phase 2) is an important route for drugs that contain what type of groups?
Where is the primary site for acetylation?
- hepatic reticuloendothelial cells
- gastric mucosa
What are two drugs that undergo N-acetylation (phase 2 conj)?
- 1. Hydralazine (Apresoline)
- --antihypertensive vasodilator
- --creates up to 20 metabolites
- 2. Clonazepam (Clonipin)
- --anticonvulsant benzodiazepine
T/F: acetylation in humans displays a bimodal character.
Who are the fast acetylators?
- Eskimos and Asians
- get treatment failure w/ isoniazid
Who are the slow acetylators?
- Egyptians and Western Europeans
- higher cure rates but could get toxic
Would you see more liver damage or hepatitis with a slow acetylator or a fast one?
fast because more rapid formation of metabolites
Which enzymes mediate methylation conjugation?
- SAM (S-Adenosylmethionine)
- COMT (catechol-O)
- Nonspecific N-methyl transferase
T/F: methylation is important in the biosynthesis of many endogenous compounds.
T/F: methylation is important in the inactivation of physiologically active biogenic amines like NE, epinephrine, dopamine, histamine, serotonin
T/F: methylation is a major pathway in the metabolism of drugs.
Which specific enzyme is responsible for the methylation of dopamine and NE?
- -inactivates flight/fight substances
What is Phase 3 metabolism?
efflux pump systems that facilitate the removal of metabolites from cells to the urine or bile
What type of drugs is there a lot of Phase 3 research going on right now for?
What are 2 drugs that undergo methylation phase 2 conjugation?
- 1. Levodopa (Dopar, Larodopa)
- --treats Parkinson's
- --must co-administer carbidopa to prevent dopamine metabolite in the periphery
- --COMT catalzes the reaction to an inactive metabolite
- 2. Terbutaline (Berthaire, Brethine, Bricanyl)
- --sympathetomimetic bronchodilator
- --also catalyzed by COMT
- ****BUT Terbutaline is not metabolized by COMT because the hydroxyl groups are in the 1,3 position and a 1,2 position is needed for the reaction to occur!!!****
What is a resorcinol?
- hydroxyls at the 1,3 position
- -not a substrate for COMT
- Terbutaline is example
What are three other drugs that undergo methylation conjugation (N and S-methylation)?
- 1. Amantadine (Symmetrel)
- --Parkinson's caused by CO poisoning
- --antiviral uses like the flu
- 2. Propylthiouracil
- --hyperthyroidism, prevents T3 and T4 synthesis
- 3. Nicotine