Transcript Lecture 16 Pharmacokinetics - Cal State LA

Pharmacokinetics in drug design
Pharmacokinetics is how a drug is Absorbed, Metabolized,
Distributed, and Eliminated. (ADME)…
Most drugs are given orally: dissolves in the GI tract and is
absorbed through the gut; passes through the liver and into the
blood stream.
% dose reaching the
bloodstream =
bioavailability
Drug is distributed to tissues and
organs throughout the body. Drug will
bind to its final target and exert its
desired action
How is pharmacokinetics monitored? Measurement of drug
concentrations in the blood or plasma
Pharmacokinetics in drug design
Pharmacokinetics in drug design
Vd = apparent volume of distribution
total blood volume = 5L in a 70kg person; 0.071L/kg
Pharmacokinetics in drug design
Pharmacokinetics influences the required dosage:
Pharmacokinetics in drug design
A drug’s success in reaching the target depends on its physical
and chemical properties
1. Chemical stability
•Does it decompose in aqueous solution?
•Does it survive stomach acid? Must it be injected?
2. Metabolic stability
•It must survive digestive and metabolic enzymes (liver)
•Any metabolites (product of drug metabolism) should not be toxic
or lose activity
•Metabolic enzyme activity (cyctochrome P450’s)
varies from individual to individual
can be affected by other chemicals (grapefruit juice inhibits
activity; cigarette smoke and brussel sprouts enhance it; other
drugs may inhibit or promote P450 enzymes = drug-drug
interactions).
2. Metabolic stability (continued)
Drug - drug interaction examples:
•Antibiotics can act as P450 inhibitors; slows the metabolism
of other drugs by these enzymes.
•Phenobarbitone (barbituate) stimulates the P450 enzymes,
accelerating the metabolism of Warfarin (anticoagulant),
making it less effective.
•Cimetidine (antihistamine) inhibits the P450 enzymes,
slowing the metabolism of Warfarin (anticoagulant).
•St. John’s wort (herbal medicine for mild to moderate
depression) promotes P450 enzymes, decreasing the
effectiveness of contraceptives and warfarin.
•Anticoagulants are bound by plasma protein in the blood, but
aspirin displaces them, which can lead to a drug overdose.
3. Successful Absorption
•Diffusion across membrane (solubility and permeability;
size, H-bonding)
•Transporters
Too hydrophilic: cant cross membranes; more easily excreted by kidneys
Too hydrophobic: poor water solubility, poorly absorbed from GI tract because
they coagulate in fatty globules.
Strategies to address hydrophilic/hydrophobic balance:
a. Use of amines with pKa = 6-8. If pKa is out of range, change
the structure of the amine to change the pKa. (2° to 3°; change
substituents on an aryl amine)
H
N H + H2O
more water-soluble;
interacts with receptors
H
N
+
H3O+
crosses membranes
b. Inject into blood supply (bypass the gut)
pKa =
-logKa
c. Take advantage of carrier proteins in cell membranes that
transport sugars, amino acids, neurotransmitters, and metal ions. If
drug resembles these, maybe the drug can be transported across
membranes.
Examples of use of carrier proteins to deliver drugs:
•Levodopa (prodrug - later) is transported by phenylalanine transporter
HO
CO2H
H
NH2
HO
CO2H
H 2N H
levodopa
phenylalanine
•Fluorouracil is transported by thymine and uracil transporters
•Lisinopril (antihypertensive) is transported by dipeptide transporters.
NH2
HO
O
N
H
N
O
Lisinopril
CO2H
d. Use of medicinal chemistry to improve hydrophobic/hydrophilic
balance.
•Change functional groups: Alcohol (ROH) versus ether (ROR’) or
ester (RO2R’)
•Change the number or size of alkyl groups
•Change rings
Example:
Cl
N
N
S
H
O
N
N
N
OH
O
Cl
Cl
Tioconazole - antifungal
nonpolar: topical
N
N
N
F
F
Fluconazole - more polar groups
introduced. More soluble, can be used
for systemic fungal infection (blood)
Pharmacokinetics in drug design
Return to 2. Metabolic stability:
•Metabolism of drugs occurs in liver, kidneys, intestine, lungs, blood
and skin, mostly catalyzed by enzymes.
•Generally, metabolic products are more water soluble than starting
compounds, so they may be readily excreted.
•Phase I Metabolic reactions include oxidations (cytochrome P450
enzymes, flavin monooxygenase, others), reductions, and hydrolyses
•Phase II metabolic reactions are the conjugation of metabolic
products to other small molecules via carboxyl, hydroxyl, thiol, and
amino groups. Conjugated products are even MORE water soluble
than the metabolites, have no toxicity or pharmacological activity
Examples of Phase I reactions on following slides...
Phase I reactions (continued)
Phase I reactions (continued)
Phase II: conjugation reactions
Metabolism of Aspirin:
Strategies to make drugs more resistant to hydrolysis and
metabolism, prolonging activity.
A. Steric “shields” to prevent the approach of a nucleophile or
enzyme to a susceptible group on the drug:
B. Isosteric/bioisosteric replacement: change an ester (more
reactive) to amide (less reactive)
O
H 3C
O
O
N(CH3) 3
acetylcholine
(neurotransmitter)
vs
H 2N
O
N(CH3) 3
Carbachol
cholinergic agonist - more stable to
hydrolysis
C. Both effects: Procaine is a short-lasting anaesthetic
because of ester hydrolysis
O
H 2N
O CH2 CH2N(CH2 CH3) 2
Procaine
CH3
NH
CH2 N(CH 2CH3 )2
CH3 O
Lidocaine
How is lidocaine protected from hydrolysis?
C. Both effects: Procaine is a short-lasting anaesthetic
because of ester hydrolysis
O
H 2N
O CH2 CH2N(CH2 CH3) 2
Procaine
CH3
NH
CH2 N(CH 2CH3 )2
CH3 O
Lidocaine
How is lidocaine protected from hydrolysis?
Steric shielding - methyl groups on phenyl ring
Ester has been changed to less reactive amide
Strategies to make drugs more resistant to metabolic enzymes
Removal of functional groups that are susceptible to metabolic
enzymes. (aryl methyl groups are oxidized to carboxylic acids and
eliminated from the body; C-hydroxylations; N and S oxidations, O
and S dealkylations, and deamination).
H 3C
O
S N
NH(CH2) 3CH3
H
O
O
O
Cl
Tolbutamide
antidiabetic
S N
NH(CH2) 3CH3
H
O
O
Chlorpropamide - longer-lasting
Strategies to make drugs less resistant to metabolic enzymes
If a drug is too resistant to metabolism, it can pose problems as
well (toxicity, long-lasting side effects). Add functional groups that
are susceptible to metabolic enzymes:
SO2 CH3
Cl
SO2 CH3
Cl
N
N
N
Ex. Anti-asthmatic drugs
metabolically suseptible:
(converted to CO 2H or CH 2 OH.
N
CH3
shorter lifetime
Prodrugs are useful approach to overcome MANY types of problems
Prodrugs are compounds that are inactive, but are converted in the
body to an active drug using the body’s metabolic enzymes!
A. Prodrugs to improve membrane permeability
1. Esters. If a carboxylic acid is important for drug binding to its
target, but it prevents the drug from crossing a membrane,
temporarily “hide” it as an ester. Once in the blood, it is hydrolized
to the active form by esterases in the blood.
CH3
H3CH2CO
O
N
H
CH3
N
O
HO
CO2H
Enalapril (prodrug) - can cross membrane
O
N
H
N
O
CO2H
Enalprilate - antihypertensive agent
2. N-methylation. Since N-demethylation is a common liver
metabolic reaction, amines may be methylated to increase
hydrophobicity. These N-methyl groups will be removed in the
liver.
O
O
N
O
NH
O
HN
O
NH
O
Hexobarbitone -prodrug
3. Take advantage of membrane transporter. Ex. Parkinson’s
disease is due to a deficiency of dopamine.
HO
HO
HO
NH2
dopamine: Too polar to
cross blood-brain barrier
HO
CO2H
H
NH2
levodopa: amino acid;
carried across membrane by
a carrier protein. Once across,
a decarboxylase removes the
carboxy group and generates
dopamine
B. Prodrugs to prolong drug activity
6-mercaptopurine is used to suppress the immune system (organ
transplants), but is eliminated from the body quickly. A prodrug
that slowly is converted to the drug allows a sustained activity.
O2N
N
N
CH3
S
N
N
H
SH
slow c onversion
N
N
N
N
H
N
N
6-mercaptopurine
Azathioprine - prodrug
C. Prodrugs to mask toxicity and/or side effects.
1. Salicylic acid is a painkiller, but phenolic -OH causes gastric
bleeding. Aspirin has an ester to mask this toxic group until it is
O
OH
hydrolyzed
O
CH
3
CO2H
Aspirin - prodrug
CO2H
salicylic acid
2. Antiviral drugs (AZT, acyclovir). Nontoxic until they are
converted to toxic triphosphates by viral enzymes in infected cells.
These phosphorylated compounds are both competetive inhibitors
and chain terminators:
O
O
CH3
HN
O
HO
N
O
O
O
HO P O P O P O
OH
O
CH3
HN
OH
O
N
O
OH
N3
N3
enzyme inhibitor
AZT
chain terminating group
Pharmacokinetics in drug design
Want to be able to look at molecular properties and predict ADME!
•Log P: water-octanol partition coefficient
•Solubility: turbidity
•pKa:
•Artificial membrane permeability
•Binding to liposomes (SPR)
•Presence of functional groups to predict metabolic products
References
Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press: New York, NY, 2001
Van de Waterbeemd, H.; Gifford, E. “ADMET in silico modelling: towards prediction paradise?” Nat.
Rev. Drug Disc., 2003, 2, 192-204.