D9 - drug distribution Flashcards
Distribution
- A drug reaches the target receptors on the tissue upon which they are located
- Concentrations need to be created to maintain a response
- The process whereby an absorbed drug is dispersed around the body via systemic circulation
- Traditional view
○ Distribution mainly occurred via passive processes (non-ionised drugs believed to be more prone to distribution)
○ Strongly influenced by physicochemical properties
§ Lipophilic drugs penetrate most, hydrophilic drugs are more restricted
○ Binding to proteins in plasma vs tissue
○ Blood flow plays a key role in tissue exposure to drugs - Emerging view
○ Drug transporters strongly regulate drug distribution
§ SLC - solute carrier transporters - transporters move drugs between compartments and into tissues
§ ABC transporters mainly move drugs out of tissues
Distribution to tissues
- After absorption, the blood plasma carries drugs to various organs the tissues
○ For oral drugs, the liver is the first stage
○ Other key tissues include the target tissue where intentions with receptors occur
○ Note that the adverse events or toxicity can occur still in other tissues- Factors that influence drug distribution include
○ Blood flow to tissues
○ Size of tissues
○ Binding to plasma proteins
○ Binding to tissue proteins
○ Permeability of tissue membranes inc. transporter expression
- Factors that influence drug distribution include
Blood flow
- For well perfused tissues, the entry of drugs is usually efficient
- Well perfused - receive a high proportion of blood flow
○ E.g. lungs - receives 100% of cardiac output
○ Kidneys, liver, GI tract, heart - significant blood flow and appreciable proportion of cardiac output
○ Rapid equilibration with plasma - after slow bolus IV
§ Rapid rise in blood concentration
§ Rapid fall after diffusion to well perfused tissue
§ After drug enters poorly perfused tissues - level falls more slowly
§ Rapid distribution to well perfused tissue followed by more gradual distribution to poorly perfused tissues
○ These tissues plus blood are often though of as a single central compartment
§ Where most of the drug goes
§ Profile of drug distribution within the compartment is homogenous
○ Skin skeletal muscle - lower blood flow - Drug distribution occurs more slowly to poorly perfused tissues
- Well perfused - receive a high proportion of blood flow
central compartment
Liver + lungs. + blood
Interstitial Fluid
- Fluid between cells and within tissues
- Most drugs easily penetrate the aqueous pores or fenestrations capillaries between endothelial cells
○ Average gap of 4nm - Most drugs are smaller than 4nm
○ Eg. Vancomycin - large drug still smaller - Ensures blood borne drugs easily access drug receptors on cell surfaces (GPCR, ion channels)
- The basal membrane is the only potential barrier to substance exchange by diffusion
○ Molecules smaller than 10kDa pass freely
○ Blood protein-bound drugs and other macromolecules are retained - Very different situation in brain capillaries, where tight junctions replace fenestrations
○ Many drugs excluded from the brain
○ Endothelial cells have very tight junctions - drugs cant diffuse
- Most drugs easily penetrate the aqueous pores or fenestrations capillaries between endothelial cells
Distribution of drugs differs according to their physiochemical properties
- The extent of cellular and tissue penetrance varies between drugs, depending on their mass, polarity and lipophilicity
- Intravascular volume - 5%
- Intracellular volume 40%
- Interstitial volume 15%
Fat - a few %
Uncommon to be evenly distributed - more likely to be confined to particular compartments
Very polar molecules wont enter into the cell
Lipophilic drugs - accumulated by fat rich tissues
Large drugs molecules - confined to the circulation
Volume of distribution and compartmental models
- Measuring plasma concentration
- Making the simplistic assumption that the body behaves as one homogenous compartments during drug distribution
○ Knowing plasma concentrations allows estimation of hypothetical volume of distribution Vdist
○ Determined by measuring plasma concentration - used C0 - time 0 plasma concentration
○ Vdist = Dose/plasma concentration
○ In reality, plasma concentrations will reflect the realities of drug distribution within the body
§ E.g. lipid soluble drugs can achieve low plasma concentrations (e.g. chloroquine - highly lipid soluble ) because the drug accumulates in peripheral fat
○
- Making the simplistic assumption that the body behaves as one homogenous compartments during drug distribution
Volume distribution
- The volume of body fluids into which the drug is apparently distributed *imaginary value
○ Doesn’t correspond to a strict anatomical site but can inform as to localisation of drug in body- Drugs distributing mainly into fat
○ Low plasma concentrations and a high Vdist - Drugs that stay in plasma
○ Highly protein bound drugs (eg. Warfarin) distribute poorly into tissues, low volume of distribution - all the drug is accounted for by concentrations in the blood○ Low VD - Drug in blood only - hydrophilic○ High VD - none in blood, drug is mainly intracellular
- Drugs distributing mainly into fat
Factors effecting Vdist
- Plasma Protein binding by drugs
Plasma protein binding
○ Plasma contains lots of protein
§ Albumin - reservoir for acidic drugs
§ Alpha1 Glycoprotein - reservoir for basic drugs
○ Plasma protein serve as carriers for natural compounds plus many drugs
○ High capacity for drug binding (non-saturable under most clinical conditions)
○ High protein binding can be problematic
§ Only free ‘unbound’ drug is active
□ Drug confined to plasma is slower to reach tissues
□ Higher doses needed to achieve therapeutic response
§ Tends to delay drug clearance by kidneys and liver
□ Has to be free to be broken down in the liver and kidneys
○ Competition by drugs causes DDIs
§ Drug-drug interaction
§ If two drugs are co-administered that compete for the same protein binding one can displace the otherLow protein binding § High short lived effect High protein binding § Low effect but more sustained exposure
Lipophilic drugs are prone to plasma protein binding
§ High LogP value
§ Most vulnerable to protein binding
§ Most drug circulates in blood while bound to plasma proteins
§ Binding sites on proteins often prefer lipophilic molecules
Human serum albumin (HSA)
§ Most abundant protein in human plasma
§ A 65 kDa monomer
□ Contains three homologous helical domains, each divided into A and B subdomains
§ 2 major drug binding sites within cavities
□ Many natural ligands including fatty acids, bilirubin
□ Many drugs with acidic features - warfarin, ibuprofen
□ Can be very high for some drugs - warfarin
Drug binding by tissue proteins
○ Some tissues express proteins that contain drug binding sites
○ Eg. Albumin is present in many cells
○ Other drug-binding proteins include
§ Ligandin - liver, kidney, intestine
§ Myosin and actin - cause significant binding to skeletal muscle for some drugs
§ Melanin - in pigmented tissues eg. Eye
○ Equilibrium between free and bound drug in tissues and plasma complicates distribution
○ Free drug concentrations usually thought to be uniform in blood and tissues throughout the body
§ Eg. Fluconazole (antifungal) - free levels in plasma resemble those in vaginal secretions, seminal secretions, CSF, breast milk, saliva etc.
- Brain penetration by drugs
○ Many of out most useful drugs are used to treat CNS disorders
○ But finding new CNS-penetrating drugs is difficult
§ Some 98% of potential CNS drugs fail due to poor brain penetrance during drug discovery research
§ Why - 2 reasons
□ Very tight junctions between endothelial cells in CNS vasculature - BBB
□ Strong p-glycoprotein expression (efflux transporter in CNS vascular endothelial cells)
® Returns many drugs to circulation - efflux transporter
- Drug partitioning into fat
○ Fat is very poorly perfused, so drug accumulation is usually limited after a single dose, even for lipophilic drugs
§ Drug accumulation can occur with chronic extended dosing
§ Stable reservoir for anabolic steroids (cannabis)
○ High accumulation can occur for extremely lipophilic drugs
§ Eg. Volatile aesthetic agents
□ E.g. thiopental, 70% of single dose accumulated in body fat
○ Obesity complicates drug disposition and dosing of lipophilic drugs
