A4: Pharmacokinetics, pt. 2 Flashcards
What is the main aim of “biotransformation” and why?
to inactivate and make non-polar / lipophilic molecules more polar and water soluble so they can be excreted by the kidneys (rather than reabsorbed in the DCTs)
What are the 3 main types of phase I reactions in biotransformation?
And what enzyme system catalyzes the majority of them?
Oxidation, Reduction and Hydrolysis
Most oxidations done by CYP450 family enzymes
There are CYP450-dependent and -independent oxidation reactions in biotransformation…
what are the -dependent ones (10 total in 5 categories)?
(prob don’t need to know them off the top of yr head but i could see an mcq asking “which of these rxns are CYP450-dependent” + needing to be able to recognize them)
- aromatic + aliphatic hydroxylation
- epoxidation
- N- or O-dealkylation
- N- or S-oxidation
- De-sulfuration, -chlorination and -amination
There are CYP450-dependent and -independent oxidation reactions in biotransformation…
what enzymes catalyze the CYP450-independent oxidations? (3)
- flavin monooxygenase
- amine oxidases
- dehydrogenases
What kind of reduction and hydrolysis reactions occur in phase I biotransformation?
- Reduction: azo-, nitro- and carbogen reduction
- Hydrolysis of esters and amides
Aside from turning active compounds into inactive metabolites…
what are 3 other situations that can occur in phase I biotransformation?
(examples?)
- active compound > active metabolite - codeine > morphine; phenacetin > paracetamol; diazepam > oxazepam
- inactive prodrug > active metabolite - enalapril > enalaprilat (ACE inhib.)
- active compound > toxic metabolite - paracetamol > N-acetylbenzoquinone
Phase II of biotransformation is a conjugation reaction.
What 5 molecules / functional groups are the phase I metabolites be conjugated with in phase II?
What is the general consequence?
- glucuronide
- sulfate
- acetyl
- methyl
- glycol
Generally further inactivates and water solubilizes the molecule
Name 3 exceptions to the general rule that phase II conjugation inactivates drugs.
(From slide, maybe not essential)
- Morphine-6-OH glucuronide is still active
- Minoxidil sulfate is the active phase II metabolite of prodrug minoxidil
- N-acetyl Isoniazid - not sure how it’s an exception, just in the slide
What 2 processes occur to increase activity of CYP enzymes when they are “induced”?
What are some examples (5) of CYP inducers?
- increased transcription CYP genes and inhibited degradation of existing CYP enzymes
- phenobarbital, rifampicin, ethanol, smoke + air pollution all induce CYP enzymes
What are 2 ways that CYP enzymes can be inhibited from metabolizing drugs?
(Give some examples of CYP inhibitors … from slide)
- Competitive Inhibition (different substrate competes with drug for same CYP isozyme) Non-substrate Inhibition (compound which is not substrate of that isozyme still inhibits it)
- Ketoconazole, cimetidine, chloramphenicol, ethinylestradiol … all inhibit CYPs
What are the terms for people whose CYP polymorphism causes them to metabolize a drug more slowly or more quickly?
Give 2 CYP isoforms for which polymorphisms have significant metabolic consequences (extra: which drugs/people).
(Many isoforms are important; these 2 are from the slides.)
- Poor metabolizers vs. extensive metabolizers
- CYP2D6 - metabolizes anti-depressants/-psychotics (haloperidol) and antiarrhythmics (propafenon); 5-10% whites are PMs
- CYP2C19 - diazepam / omeprazole; 15-20% asians are PMs
Give an example of a phase II biotransformation reaction for which enzyme polymorphism plays an important role.
What is its significance?
- N-acetylation of drugs such as isoniazid, procainamide (Na channel blocker; anti-arrhythmic) and nitrazepam
- Many people are “slow acetylators” (90% egyptians, ~55% whites, 15% asians)
- Isoniazid has significant side fx… hepatotoxicity + incr. SLE risk
What are the 3 main processes in renal excretion / elimination of drugs?
- Glomerular Filtration - non-protein bound drug filters thru glomerulus; lipid solubulity and pH do not affect this, but GFR / protein binding do.
- Active Tubular Secretion/Reabsorption - PCT secretion by non-selective (+ thus competitive) anion/cation transporters
- Passive Diffusion - in DCT, nonpolar / uncharged molecules can be reabsorbed; can be manipulated by changing urine pH (discussed in previous cards)
What other routes can drugs be eliminated by?
(examples?)
(first route is most signifcant / in slides; others just from book)
- Biliary Excretion - digoxin, morphine, chloramphenicol + ethinylestradiol eliminated via bile in feces
- Lungs - anesthetic gases
- Breast Milk
- Sweat, Saliva, Tears, Hair and Skin
What kind of kinetics does the metabolism of most drugs follow? Explain it.
What is the equation for this?
(on answer card, image shows a drug concentration vs. time graph, both normally and semi-logarithmically … just for… fun)
First-Order / Linear Kinetics
- rate of drug metabolism/elimination is directly proportional to concentration of free drug
- a constant fraction of drug is eliminated per unit time
- V = Vmax * [C] / Km
- (V = rate of metab. / Vmax = rate when system is saturated / [C] = drug conc. / Km = conc. when rate is 1/2 Vmax)
What are zero order / non-linear kinetics?
When does it occur? (Examples?)
What are the consequences of zero order kinetics for elimination speed?
- rate of elimination is independent of concentration
- occurs when the elimination process is saturated either in all or part of the concentration range (occurs with ethanol and phenytoin)
- means that elimination is slower than first-order and half-life can’t be determined (fraction of drug eliminated per unit time is not constant)
What is clearance?
How is it calculated?
the volume of blood cleared of a drug by metabolism and excretion per unit time
total body clearance = metabolic clearance + renal clearance + other clearances (biliary, etc.)
CL = M * AUC
M = dose, AUC = area under (conc. vs. time) curve … more on AUC later
What is the elimination coefficient (Kel) of a drug?
(this was a minor point on the 1st order kinetics slide… maybe not super important but it shows up in other calculations)
a value describing the partial drop of concentration per unit time
calculated as Kel = CL / Vd
CL = clearance, Vd = volume of distribution
What is half life in pharmacokinetics?
Its equation?
- the time interval during which the concentration of a drug in the body changes by 50%; note that this can refer to an increase or decrease in concentration depending on whether absorption/distribution or elimination is being observed
- directly proportional with Vd, inversely with clearance
- T1/2 = Vd / CL * ln 2… (ln 2 = natural log of 2)
What is AUC (Area Under Curve) in pharmacokinetics?
What does this value represent?
How is it measured?
And calculated?
- AUC is the integral (calculus term, sorry) of a concentration vs. time curve.
- AUC represents total drug exposure over time and is proportional to the total amount of drug absorbed by the body.
- AUC is measured by taking blood concentrations of a drug at various time points, plotting the conc. vs. time curve and estimating the area under the curve.
- It can be calculated as AUC = M / CL… (M = dose, CL = clearance)
- (There was a calculus-y equation for this on the slide, but I don’t think we need to know it or be able to calculate it that way…)
How can AUC be practically used in pharmacology?
- Bioavailability Determination - can use it to determine absolute (AUC of drug via administration method in question vs. via IV admin) or relative bioavailability (AUC of one formulation of a drug vs. another, via same admin method)
- Therapeutic Monitoring - useful in monitoring therapy of drugs with a narrow therapeutic window (ex: gentamicin, with its nephro-/ototoxicity)
What is the “two compartment open model” as it relates to the concentration vs. time curve?
(I’ll call it the 2COM in the answer card to save space)
- 2COM describes the conc. vs time curve as having two phases: the rate of α phase describes the i_nflow of the drug into the peripheral compartment_ (fat, skin, muscle), the rate of β phase describes the rate of elimination (a third γ phase may represent the deep compartment)
What is the dominant half-life?
Using the 2 compartment open model and the concept of dominant half-life, which part of the curve provides more useful information about how the drug will accumulate over multiple doses?
- Dominant half-life is the the half-life during the phase with the largest AUC (usually the terminal β-phase)
- The half-life of the terminal phase (β-phase) is important in determining how multiple doses will accumulate
What is the “steady state concentration” (Css) of a drug, in terms of continuous and intermittent administration? How can it be calculated?
What is the main determining factor of Css?
- Steady state concentration (Css) is the concentration of the drug in the plasma when the rate of infusion equals the rate of elimination.
- Infusion rate (R0) is the main determinant of Css and is a dose per unit time value.
-
Css = R0 / CL… (CL = clearance)
- So Css is inversely proportional to clearance … makes sense.
