D9 - drug distribution Flashcards

1
Q

Distribution

A
  • 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
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2
Q

Distribution to tissues

A
  • 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
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3
Q

Blood flow

A
  • 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
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4
Q

central compartment

A

Liver + lungs. + blood

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5
Q

Interstitial Fluid

A
  • 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
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6
Q

Distribution of drugs differs according to their physiochemical properties

A
  • 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 %
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7
Q

Uncommon to be evenly distributed - more likely to be confined to particular compartments

A

Very polar molecules wont enter into the cell
Lipophilic drugs - accumulated by fat rich tissues
Large drugs molecules - confined to the circulation

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8
Q

Volume of distribution and compartmental models

A
  • 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
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9
Q

Volume distribution

A
  • 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
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10
Q

Factors effecting Vdist

A
  1. 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 other
     Low protein binding 
         § High short lived effect 
     High protein binding 
         § Low effect but more sustained exposure
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11
Q

Lipophilic drugs are prone to plasma protein binding

A

§ 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

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12
Q

Human serum albumin (HSA)

A

§ 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

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13
Q

Drug binding by tissue proteins

A

○ 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.

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14
Q
  1. Brain penetration by drugs
A

○ 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

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15
Q
  1. Drug partitioning into fat
A

○ 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

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16
Q

Membrane transporters and drug distribution

A
  • Major role in drug distribution
    ○ Act as pumps to facilitate drug movement across lipid membranes
    ○ Can be efflux (outward) or influx transporters
    ○ Tissue expression influences how well a drug penetrates a particular tissue
    § Governs Vdist of many drugs
    ○ Some key transporters include
    § OAT - organic anion transporter
    § OCT - organic cation transporter
    § P-gp
17
Q

○ Some key transporters include

A

§ OAT - organic anion transporter
§ OCT - organic cation transporter
§ P-gp

18
Q

Role of influx transporters in hepatic drug uptake

A

○ The liver = first port of called for drugs in portal blood that drains GIT
○ Strong expression of transporters - especially influx - bring drugs out of systemic circulation and into the liver to be detoxified
○ Cation and anionic drug transporters - accumulate drugs
○ Significant contributor to the volume of distribution
○ Detoxifies many foreign substances
§ Protects body against ingested xenobiotics
○ Needs efficient uptake processes to accumulate foreign substances
§ Many organic anion and cation transporters expressed in basolateral hepatocyte membranes
§ Drug accumulation via transporter-mediated hepatic uptake contributes to Vdist

19
Q

OCT1/2 - organic cation transporters

A

○ Important many drugs (cations) into the liver
○ A key drug substrate is metformin
§ Widely used diabetes drug
§ Lowers blood sugar levels in diabetes
○ Role of OCT1/2 in metformin PK tested in OCT1/2- knock out mice
§ Lack of transporter
□ Decreases liver : plasma drug ratio
□ Increase plasma concentration - risk of side effects
□ Lowers Vdist
○ Knocking out the transporter reduced the accumulation of the drug in the liver - plasma concentrations were elevated - more drug in plasma because it is not getting stuck in the liver
○ Effects DDI drug-drug interaction - if you administer two drugs competing for the same receptor one could outcompete the other and change the Vdist