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Introduction

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Surely Surely

on 29 October 2014

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Transcript of Introduction

Introduction
Properties of drugs
and membrane permeation

Drug membrane permeation
General pharmokinetics
Goal: prevent, cure, control diseases

Pharmokinetics
: what body does to drug (quantitative description of drug concentrations in body over time)
Specific routes of administration affect optimum dose.

Pharmodynamics
: what drug does to body
Effects of drugs:
related to dose
better predicted by concentration achieved in blood/target tissue (than dose)
related to length of time in body
Drug disposition processes (ADME) and terminology
Site of administration
Absorption
Bioavailability
Plasma
Tissue
Volume of distribution (Vd)
metabolism
elimination
distribution
Clearance (CL)
Half-life
Broad classification
Small molecules
Organic - natural or synthetic
300-900 kDA

Peptides
tens of amino acids (small peptidic hormones)
Proteins
Enzymes, hormones, antibodies

Oligonucleotides
antisense therapeutics
*All ADME processes depend on drug movement across membrane
Passive diffusion


Facilitated diffusion
(facilitated transport)

Active transport


Endocytosis
Barriers
Gastrointestinal mucosa
Skin, corneal epithelia
Blood capillaries
Placenta
Cells of the organs
Aqueous Pores
Water pores of 8 A allow also passage of:
Small (< 150kDa) hydrophilic molecules

Concentration gradient

Membrane plays a passive role; no energy is required beyond that necessary to maintain its integrity.

Rate of drug transport is proportional to Concentration gradient.

Frequently follows first-order (linear) kinetics:
Rate of transport = k[Conc]
where k is a first-order constant.

Process is independent of the presence of other compounds.

Transport determined by physicochemical properties of the drug:
lipid solubility and degree of drug ionization
Passive diffusion
Fick's law
Rate diffusion =
P * A * C
d
P = permeability (drug's physicochemical properties)

A = surface area

C = concentration gradient

d = membrane thickness
Size
Lipophilicity
Charge (pH)
Chemical substituents
Increase lipophilicity
Alkyl groups
Carbons Rings
Aromatic Rings
Halogens
Decrease lipophilicity
Nitrogen (amides)
Oxygen (alcohols, aldehydes, carboxylic acids)
Sulfur
Phosphates
Higher partition coefficient = more dissolved in Octanol = higher lipophilicity
Measured by Partition Coefficient
Drug Ionization, pH, and Partition
Rate of passive diffusion depends on concentration -
of diffusable form of drug.
May be different from "total" concentration of drug

Un-ionized form is more diffusable: Ionization depends on pH and pKa of drug.
A-
HA
B
BH+
HA <-> A-
B <-> BH+
Very different from diffusion!
Physicochemical properties for facilitated transport
Hydrophilicity
ionized
Metabolized into conjugate (phase II)

*Don't
need
to possess these properties to be a substrate
cytosol
ER
Mitochondria
Glucuronidation
Sulfation
Glutathione conjugation
Acetylation
Glutathione conjugation
UGT
SULT
NAT
GST
GST
UDP-glucuronic acid
PAPS
GSH
Acetyl CoA
GSH
Full transcript