Chemical Methods for Improving PK Flashcards
the main parameters of optimizing pharmacokinetics are
aqueous solubility, chemical and metabolic stability, intestinal absorption
structural bioisoteric qualities
size shape hbonding
receptor interaction bioisoteric qualities
hbonding, electronic
log P < 5 makes for
increased oral bioavailibility
can you add or remove functional groups in the pharmacophore to improve hydrophylicity/hydrophobicity?
not so much, the pharmacophore is important!
T/F: Adding or removing functional groups is a practical method for improving hydrophobicity?
F
adding polar groups ______ the logP
decreases
modifying _______ is a way of altering hydrophobicity
potential ionization sites
pH of stomach
1-4
pH of small intestine
7-8
amide bonds are ____ to stomach pH
very susceptible
use of ____ can help prevent amide hydrolysis
amide bond mimics
name three ways to prevent degridation by peptidases and esterases
bond mimics, steric shields, bioisoteres
steric shields use ___ to ______
a large steric group/ block enzyme from degrading
problem of steric shields:
adding a large FG often changes PK properties
to prevent degredation, we use ___ to make compound more stable and resist cleavage
electron donating
_ in liver metabolizes many drugs
CYP450
General metabolism: ______ then _______
oxidation/ conjugation
CYP450 wants to make compounds ______
more water soluble
CYP450 metabolizes at two main sites for aromatics:
methyl groups, para position to R group
Solution to CYP450 metabolism:
use bioisoters
species difference in metabolism is a major consideration in preclinical testing of prodrugs
true
Type I prodrugs:
intracellular site of conversion
Type IA prodrugs:
converted in therapeutic target tissue
Type IB prodrugs:
converted in metabolic tissues
Type II prodrugs
extracellular site of conversion
Type IIA produrgs:
converted in GI fluid
Type IIB prodrugs:
converted in systemic circulation
metabolic tissues are:
liver and lungs
liberation of prodrug:
active drug molecule is intact within overall structure of the prodrug
bioactivation of prodrug:
must be converted into a new chemical structure - can be chemical or metabolic conversion
ester prodrugs are commonly used to
enhance membrane permeability of easily ionizable carboxylic acid
rate of cleavage is affected by ________ of ester
electronic effects
_____ speed up cleaveage of ester prodrugs by making the ester ___
electron withdrawing groups/ unstable
_____ speed down cleavage of ester prodrugs by making the ester ____
electron donating groups/ stable
antibody drug conjugates:
prodrugs tied to antibodies –> target only certain cells
trojan horse prodrugs:
allows a compound to get into cell and then convert to active form
