Lecture 3: membrane permeability and partitioning of drugs Flashcards
Hydrophilic groups
-lipophobic
-love water
-usually polar and capable of H bond formation
Hydrophilic functional groups
-alcohol
-carboxylic acid
-amine
-ketone
-amide
-ester
Hydrophobic groups
-lipophilic
-hate water
-usually non-polar hydrocarbons
Hydrophobic functional groups
-methyl
-chloro
-phenyl
-hexyl
-cyclohexyl
Hotseat: Which molecule is more hydrophobic?
The one with a CH3 group instead of OH group
Hotseat: Which molecule is more hydrophobic?
the one with the hexyl group instead of alcohol group
Lipinski’s rule of five
-describe druglikeness (orally active drugs)
-based on observation that orally active drugs are usually small and lipophilic
Lipinski’s rule
-no more than 5 H-bond donors (-OH, -NH)
-no more than 10 H-bond acceptors (O, N)
-mass less than 500
-LogP < 5
LogP
-Log value of partition coefficient (P)
-measure lipophilicity
-most drugs have values from -1 to 4
LogP < 0
drug favors water
LogP = 0
equal
LogP > 0
drug favors 1-octanol
larger LogP
-more lipophilic
-more hydrophobic
typical LogP values
-1 to 4
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?
100:1
Activity versus LogP
-parabola curve opening downwards
optimal logP (logP0)
-logP value relating to maximum drug activity
Lipophilicity
-improves permeation
-too much can hinder crossing
Drug Partitioning Through Multiple Compartments
Separated by Membrane Barriers
LogP= 0 diffuses the quickest and more evenly
LogP= 3 diffused similarly to -3 but sticks around the membrane bc of attraction
Calculated LogP (CLogP)
-sum of pi values of the molecule’s fragments
Fragments
-additive
-structural
LogP of benzene is 2.13. What is ClogP of the following compound?
ClogP = sum of pi values of:
-I
-OH
-CH3
-ONH2
=1.65
Is this example molecule (1.65) more or less hydrophobic than benzene (2.13)?
less hydrophobic
Acidic and basic drugs in the aqueous phase
-may exist in ionic and neutral forms
Organic phase
-drug only in neutral form
-[HA]
Partitioning of acidic and basic drugs
-dependent on pH
-increase in ionization leads to accumulation of drug in aqueous phase
Increase in ionization
= accumulation of drug in aqueous phase
Partition coefficient (P)
= [HA]org / [HA] aq
Distribution coefficient (D)
= [HA] org / [HA]aq+[A-]aq
-more informative than P
Organic
HA
Aqueous
HA <-> A- + H+
Drug HA is an acidic drug with
logP = 2 and pKa = 4
At pH=1:
D ~ P
-[A-]aq negligible compared to [HA]aq
Drug HA is an acidic drug with
logP = 2 and pKa = 4
At pH=7:
D «_space;P
-[A-]aq much greater than [HA]aq
Distribution of an ACIDIC drug: at higher pH
-logD «_space;logP
-drug may NOT cross lipid membrane well
Distribution of an ACIDIC drug: when pH»_space; pKa
LogD = LogP - (pH - pKa)
Distribution of a BASIC drug: at LOWER pH
logD «_space;logP
-may NOT cross lipid membrane well
Distribution of a BASIC drug: when pH «_space;pKa
LogD = LogP- (pKa - pH)
Drug B is a basic drug with
logP = 2 and pKa = 7
at pH= 10
D ~ P
[BH+]aq negligible to [B]aq
Drug B is a basic drug with
logP = 2 and pKa = 7
at pH = 4
D «_space;P
[BH+]aq is much greater to [B]aq
[HA]
[B] in basic drugs
[A-]
[BH+] in basic drugs
Graph of Distribution of an acidic drug
decreasing log function as pH increases
Graph of Distribution of a basic drug
increasing log function as pH increases
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?
1:10
Which of the following is a hydrophobic functional group?
-CH2CH3
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?
LogD is much greater than 3.18 at pH 10.0.
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
2.02
Select the most lipophilic (hydrophobic) compound from the following. The table of π values is given for your information.
groups with positive pi values