Lecture 3: membrane permeability and partitioning of drugs

Question 1

Hydrophilic groups

Answer 1

-lipophobic
-love water
-usually polar and capable of H bond formation

Question 2

Hydrophilic functional groups

Answer 2

-alcohol
-carboxylic acid
-amine
-ketone
-amide
-ester

Question 3

Hydrophobic groups

Answer 3

-lipophilic
-hate water
-usually non-polar hydrocarbons

Question 4

Hydrophobic functional groups

Answer 4

-methyl
-chloro
-phenyl
-hexyl
-cyclohexyl

Question 5

Hotseat: Which molecule is more hydrophobic?

Answer 5

The one with a CH3 group instead of OH group

Question 6

Hotseat: Which molecule is more hydrophobic?

Answer 6

the one with the hexyl group instead of alcohol group

Question 7

Lipinski’s rule of five

Answer 7

-describe druglikeness (orally active drugs)
-based on observation that orally active drugs are usually small and lipophilic

Question 8

Lipinski’s rule

Answer 8

-no more than 5 H-bond donors (-OH, -NH)
-no more than 10 H-bond acceptors (O, N)
-mass less than 500
-LogP < 5

Question 9

LogP

Answer 9

-Log value of partition coefficient (P)
-measure lipophilicity
-most drugs have values from -1 to 4

Question 10

LogP < 0

Answer 10

drug favors water

Question 11

LogP = 0

Answer 11

equal

Question 12

LogP > 0

Answer 12

drug favors 1-octanol

Question 13

larger LogP

Answer 13

-more lipophilic
-more hydrophobic

Question 14

typical LogP values

Answer 14

-1 to 4

Question 15

The logP value of drug A is 2. what is the ratio of the concentration
of the drug in the organic phase to that in the aqueous phase?

Answer 15

100:1

Question 16

Activity versus LogP

Answer 16

-parabola curve opening downwards

Question 17

optimal logP (logP0)

Answer 17

-logP value relating to maximum drug activity

Question 18

Lipophilicity

Answer 18

-improves permeation
-too much can hinder crossing

Question 19

Drug Partitioning Through Multiple Compartments
Separated by Membrane Barriers

Answer 19

LogP= 0 diffuses the quickest and more evenly
LogP= 3 diffused similarly to -3 but sticks around the membrane bc of attraction

Question 20

Calculated LogP (CLogP)

Answer 20

-sum of pi values of the molecule’s fragments

Question 21

Fragments

Answer 21

-additive
-structural

Question 22

LogP of benzene is 2.13. What is ClogP of the following compound?

Answer 22

ClogP = sum of pi values of:
-I
-OH
-CH3
-ONH2
=1.65

Question 23

Is this example molecule (1.65) more or less hydrophobic than benzene (2.13)?

Answer 23

less hydrophobic

Question 24

Acidic and basic drugs in the aqueous phase

Answer 24

-may exist in ionic and neutral forms

Question 25

Organic phase

Answer 25

-drug only in neutral form -[HA]

Question 26

Partitioning of acidic and basic drugs

Answer 26

-dependent on pH -increase in ionization leads to accumulation of drug in aqueous phase

Question 27

Increase in ionization

Answer 27

= accumulation of drug in aqueous phase

Question 28

Partition coefficient (P)

Answer 28

= [HA]org / [HA] aq

Question 29

Distribution coefficient (D)

Answer 29

= [HA] org / [HA]aq+[A-]aq -more informative than P

Question 30

Organic

Answer 30

HA

Question 31

Aqueous

Answer 31

HA <-> A- + H+

Question 32

Drug HA is an acidic drug with logP = 2 and pKa = 4 At pH=1:

Answer 32

D ~ P -[A-]aq negligible compared to [HA]aq

Question 33

Drug HA is an acidic drug with logP = 2 and pKa = 4 At pH=7:

Answer 33

D << P -[A-]aq much greater than [HA]aq

Question 34

Distribution of an ACIDIC drug: at higher pH

Answer 34

-logD << logP -drug may NOT cross lipid membrane well

Question 35

Distribution of an ACIDIC drug: when pH >> pKa

Answer 35

LogD = LogP - (pH - pKa)

Question 36

Distribution of a BASIC drug: at LOWER pH

Answer 36

logD << logP -may NOT cross lipid membrane well

Question 37

Distribution of a BASIC drug: when pH << pKa

Answer 37

LogD = LogP- (pKa - pH)

Question 38

Drug B is a basic drug with logP = 2 and pKa = 7 at pH= 10

Answer 38

D ~ P [BH+]aq negligible to [B]aq

Question 39

Drug B is a basic drug with logP = 2 and pKa = 7 at pH = 4

Answer 39

D << P [BH+]aq is much greater to [B]aq

Question 40

[HA]

Answer 40

[B] in basic drugs

Question 41

[A-]

Answer 41

[BH+] in basic drugs

Question 42

Graph of Distribution of an acidic drug

Answer 42

decreasing log function as pH increases

Question 43

Graph of Distribution of a basic drug

Answer 43

increasing log function as pH increases

Question 44

The logP value of drug A is -1. what is the ratio of the concentration of the drug in the organic phase to that in the aqueous phase?

Answer 44

1:10

Question 45

Which of the following is a hydrophobic functional group?

Answer 45

-CH2CH3

Question 46

The structure of naproxen is shown below. The pKa of the drug is 4.15, and the LogP is 3.18. Which of the following statements about LogD is INCORRECT?

Answer 46

LogD is much greater than 3.18 at pH 10.0.

Question 47

LogP of benzene is 2.13. What is ClogP of p-methylphenol? The structure of the compound and the table of pi values are given for your information. pi values: 0.56 and -0.67

Answer 47

2.02

Question 48

Select the most lipophilic (hydrophobic) compound from the following. The table of π values is given for your information.

Answer 48

groups with positive pi values