pharmacokinetics 1

Question 1

absorption

Answer 1

1) from site of administration
2) cross membranes by passive movement or active transport
- majority rely on diffusion - non-specific
- majority of the rest - specific carrier
- small water-soluble molecules - aqueous pores
- pinocytosis - large molecules

Question 2

distribution

Answer 2

1) within the body to organs and tissues

Question 3

metabolism

Answer 3

1) biotransformation of drug, often inactivating

Question 4

excretion

Answer 4

1) removal of drug metabolite from body

Question 5

diffusion through lipid membranes

Answer 5

1) lipid solubility can be determined from aqueous fractions at equilibrium (partition coefficient)
2) the higher lipid solubility, better interactions and passing through the membrane
3) but very high, means it may be retained in the membrane itself
4) drug design depends on this factor
5) weak acids and bases determine ionization state, another factor which allows drugs to pass membranes

Question 6

pH and ionization

Answer 6

1) weak acid and bases (most drugs)
- ionized or uncharged depending on pH
2) ionized dissolve in aqueous, uncharged pass through membranes
3) henderson-hasselbalch equation

pH - pKa = log [B]/[BH+]
- pKa is known for most drugs and most bodily fluid pH is known

pH - pKa = log [A-]/[HA]

Question 7

a calculated problem

Answer 7

1) weak acid drug pKa= 4.5 and in the intestine where pH = 5.5
- what % is in permeant form?

5.5 - 4.5 = log[A-]/[HA] = 1
take antilog = 10

10:11 deprotonated to protonated, meaning this is 9/1% protonated
- unlikely to dissolve

Question 8

for estimation

Answer 8

1) use protonation table

Question 9

pH partition and ion trapping

Answer 9

1) when ionization occurs, it is less likely to cross the membrane
2) aspirin in the stomach is unionized, and more lipid solubility => enters blood and is deprotonated => dissolves readily and is retained in the blood

Question 10

theoretical partition of weak acid and weak base drugs in aqueous compartments of varying pH

Answer 10

1) basic drug sits in a compartment with low pH, and vice versa
- “ion trapping”
2) diffusion is random, so at equilibrium, equal fractions of non-ionized drug may theoretically be found in each compartment if we ignore drug metabolism and excretion

Question 11

organic cation and anion transporters

Answer 11

1) passive movement of solutes down gradients
- facilitated diffusion
2) structurally related organic cation transporter (OCT) and organic anion transporter (OAT)
- directional
3) important for transport at BBB, GIT, and renal tubule

Question 12

ATP binding cassette (ABC)

Answer 12

1) P-glycoproteins (P-gp)
- major group
- drug resistance and cancer
- present in high quantity in intestines, renal tubular BB membranes, bile canaliculi
2) susceptible to polymorphic variation
- patient responses vary
3) ABC and SCL may be expressed in different surfaces on polar cells
- some move in, and some out

Question 13

plasma proteins and drug bindings

Answer 13

1) almost all drugs reversibly bind plasma proteins
2) level of binding depends on affinity
- 1-2% - 99%
3) equilibrium is maintained when drug is taken up into tissues and bound drug is released from proteins
4) when drug saturation occurs, it makes a big difference to free drug concentration
- most drugs aren’t in saturating concentrations

Question 14

distribution - compartments

Answer 14

1) aqueous compartments
- cytoplasm is chief reservoir for water soluble drugs
- body fat 20%, interstitial water 16%, intracellular water 35%, transcellular fluid 2%, plasma water 5%

Question 15

volume of distribution

Answer 15

1) apparent volume of distribution, Vd
2) D = dose, C0 = plasma concentration at time zero
3) volume of fluid required to contain the total amount, (D), of drug at the same concentration as present in the plasma
4) plasma drug levels measured for this estimation

Vd = D/C0
high volume: left circulation
low volume: still in circulation

Question 16

blood brain barrier

Answer 16

1) solute passage is prevented by lack of fenestrations
2) tight cell junctions so solutes must pass through two lipid membranes
3) must be highly lipophilic to pass
4) most drugs and large molecules are excluded
5) some AA, amines, purines are transported by carriers

Question 17

metabolism

Answer 17

1) a drug effect is not sum of pharmacological ability, it is also described with metabolism
2) metabolism in liver, excretion in kidney
3) make is less water soluble, change structure to reduce intrinsic efficacy
4) phase I => redox reaction
- oxidation, hydroxylation, dealkylation, deamination, hydrolysis
- increase water solubility
5) phase II => conjugation of side chains
- polar molecule that is readily excreted

Question 18

first pass effect and pro-drugs

Answer 18

1) most drugs metabolized in liver
- reduces bioavailability of drug (reaching systemic circulation)
- pro-drugs: e.g. diazepam demethylation (gain activity after being metabolized)
2) first pass effect - absorption from SI direct to hepatic portal vein
- lidocaine cannot be admin orally bc it will reach the liver and get metabolized by enzymes
3) generally microsomal enzymes by some non microsomal
4) drug metabolizing enzymes in many tissues
- lung, kidney, GIT, placenta, and GI bacteria

Question 19

phase I

Answer 19

1) add reactive residue to the molecule
- can make active drug or toxic metabolite
2) often it is -OH / hydroxyl
- conjugation site can be targeted by phase II
3) cytochromes are situated in liver
4) happens more for NONpolar drugs, as they need to cross cell membrane to reach the enzymes
5) cyt p450
-net effect is addition of OH or oxygen
- genetic variation in this determines drug response
- grapefruit juice can inhibit p450 enzymes
- not all phase I involves these enzymes (cytochrome and plasma enzymes)

Question 20

phase II

Answer 20

1) conjugation
- inactive produce
- also mainly in the liver
- using reactive residue, conjugates are added to the drug
2) ex. acetaminophen => glucoronate ad sulfate conjugates
- some metabolized by p450, responsible for toxicity (NAPQI)
- NAPQI is usually conjugated with glutathione, but in excess, it is not cleared and causes liver toxicity
3) bilirubin is also conjugated with glucuronidation
4) UDP glucoronyltransferase allows for conjugation

Question 21

excretion

Answer 21

1) hepatic route
- various substances including drugs transported from plasma to bile via SLC and P-gp transporters
- enterohepatic circulation can reuptake excreted drugs
2) renal route
- glomerular filtration
- active tubular secretion
- passive diffusion across tubular epithelium

Question 22

renal excretion

Answer 22

1) molecules smaller than mv 5000-15000 readily pass and are cleared by glomerular filtration
- plasma proteins such as albumin do not pass (too large)
- plasma protein bound drug is therefore not filtered and retained in circulatory
- ex. warfarin is 98% bound
2) tubular secretion
- transport via carriers (OAT, OCT)
- can be antagonized
3) passive diffusion
- highly lipophilic drugs or those non-ionized in urine may be resorbed

Question 23

renal excretion - pH and ionization

Answer 23

1) pH of urine can change dramatically
2) artificial alteration of pH can regulate drug control
3) up to 99% of water exiting the circulation is reabsorbed
- drugs are passively absorbed, usually lipophilic ones
4) ion trapping of basic drugs in acidic urine, and vice versa

Question 24

clearance from liver and kidneys

Answer 24

1) indicator of drug removal from plasma
- volume of drug cleared per time
2) independent of drug kinetic parameters
- clearance is a constant
- measure of the organs of elimination function
3) total body clearance is sum of all body clearance mechanisms
- renal clearance may be close to total body clearance!!

Question 25

primary excretion is via

Answer 25

1) urine but also feces, breath, sweat, saliva, tears, and breast milk

Question 26

plasma clearance is

Answer 26

1) volume of plasma cleared of drug per unit time
- ml/min
-Cl: rate of removal/plasma concentration of drug
- for accuracy, resorption and glomerular filtration rate should also be accounted for