Lecture 9 PCL201 Drug Distribution

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1 Lecture 9 PCL201 Drug Distributin Where d drugs distribute? Drug distributin (and ptentially cncentratin) will depend n bld flw and the physichemical prperties f the chemical Lipid and water slubility Inizatin Size (fr hydrphilic) Play a rle in distributin, ability t crss membranes Bld flw t tissues Cardiac Output Tissue vlume What is vlume f distributin? Vlume f Distributin (Actual) Anatmical vlume accessible t the drug E.g. Charged cmpund (ECF can t diffuse acrss membrane) vs. uncharger nnplar cmpund (can distribute t different areas, TBW) ECF vs TBW = 12L vs 42L Vlume f Distributin (Apparent) The hypthetical vlume necessary t cntain hmgenus cncentratin in bld, plasma, r water. Vd can be measure and calculated fllwing IV injectin f knwn cmpunds. Large Vd nt cncentrated (lw MW, hydrphlic (lipid sluble), access t mre thrugh diffusin thrugh membranes) Intermediate Vd cncentrated in a smaller area ECF (can t readily crss membranes) Small Vd quite cncentrated Drug is cncentrated in plasma cmpartment Vd prvides infrmatin n where a drug will be fund and where it wn t be fund. Why is Vd imprtant? Knwing the Vd f a drug allws us t calculate the dse required t achieve a desired plasma cncentratin. In practice: Wrks with respect t calculating drug cncentratins Des nt prvide nfrmatin n if the drug is effective Hw can we calculate Vd? Iv injectin fllwed by measuring drug cncentratins at specific time pints. Use semilg plt, extraplate t t=0 (remember t use anti-lg) What infrmatin des Vd prvides? Increased Vd, nt cncentrated, drug equilibrating t ther places utside f plasma, nt fund in plasma t a great extent. Vd nt necessarily a measure f physical vlume, rati f drug in cmpartments utside plasma relative t plasma, allws fr dse estimatin

2 Increased Vd, lw cncentratin fund in plasma cmpartment, increased Vd, decreased cncentratin fund in plasma, make it t prly accessible regins. Drugs with very large Vd have higher cncentratins in extravascular tissue than in vascular cmpartments (plasma) and are NOT hmgenusly distributed. Drugs that are cmpletely retained within vascular cmpartments have very lw Vd equal t r less than bld cmpnent distributed in vascular fluid. Lw Vd, in plasma, large, hydrphbic, bund t prteins in plasma Drug Distributin in ECF ECF = plasma (intravasular and ISF) Many cmpunds are permeable t capillary membranes and act at cell surface and are inactive inside the cell. Many cmpunds d NOT gain access t inside the cell Mannitl can be used t measure ECF mpartment: High Vd, High cncentratin in extravascular tissues relative t plasma, nt hmgenusly distributed. Drug Distributin in Bld Plasma cmpnent (intravascular) where cmpunds are disslved in water Plasma prtein bund cmpunds becme bund thrugh nncvalent interatin α-glycprtein (binds t weakly basic drugs), albumin(binds t weakly acidic drugs), and lipprteins Drug ncentratins measure in plasma/serum and usually will be dependent n the hematcrit. Hematcrit - & packed erythrcytes: amunt f frmed bld cells. Average cunt: Men ~50, Wmen ~40 It is imprtant t knw if drug is in plasma knw if drug can reach target get dsing infrmatin need t be in plasma t be excreted Plasma Plasma prtein bund drugs, high drug cncentratins in plasma s Vd small ECF Large water sluble drugs TBW Small drugs, rapid equilibratin between all cmpartments Tissue cncentratin drugs that bind tssue Factrs affecting Vd 1. Intravascular a. Plasma prteins 2. Extravascular a. Cellular prteins, tissue, bne, muscle 3. Adipse a. Lean vs. bsess bdy weight b. Female vs. Male (% bdy fat) 4. Enterhepatic Circulatin (bld vessels that feed liver can extend duratin f actin)

3 5. Redestributin Plasma Prtein binding Nt all drugs disslve in plasma water sme assciate with bld cmpnents: albumin, glbulins, lipprteins and erythrcytes, acid glycprteins Evans blue IV injectin binds strngly t plasma albumin, s entire dse in plasma. Causes misleading small Vd because nly want t measure unbund drug which will equilibrate t rest f bdy. Plasma prtein binding must be taken int accunt when cnsidering Vd. Alters drug-plasma cncentratin Alters effective drug cncentratin fr target Will nt necessarily elimated as readily Unbund Drug can g t Site f actin: capillary walls, cell membrane, intracellular site, still in plasma t bind t prtein, decrease free disslved drug able t crss membrane Site f eliminatin: glmerular filtratin, renal tube secretin, hepatic bitransfrmatin, bilary secretin % Free drug depends n 1. Kd f drug (affinity) 2. Ttal drug cncentratin 3. albumin cncentratin If lw Kd, at lw drug cncentratins, mstly bund e.g. phenylbutzne 100 times greater inttal plasma than in plasma water and ECF. It is bund t prteins, very little freely flating in plasma water. As drug cncentratins increase, prtein becmes saturated and free drug cncentratin increases. Tw imprtant plasma prteins fr drug binding Albumin Negatively charged s binds t weak acids (but cnsidered nn-specific) Albumin levels are generally lwer in disease states, therefre lwer ttal drug cncentratin, increased free drug cncentratin Orsmucid (α1-acid glycprtein) Psitively charged, s binds t weak bases Increased levels during perids f acute inflammatin Plasma prtein binding is mre imprtant fr drugs highly bund at lw cncentratin (high affinity) Pharmacdynamically imprtant Decrease cncentratin available t act Saturatin f binding ccurs as drug cncentratin increases, therefre prprtin f unbund drug cncentratin increases with higher dses

4 Extend duratin f actin May play a rle with drug interactins Fr drugs that are bund at high drug cncentratins, free drug cncentratins increases less rapidly than dsing rate suggests, until prtein binding appraches saturatin Takes mre drug befre binding t plasma prtein As a result f prtein binding Smaller cncentratin available fr drug target Drug efficacy effected Eliminatin slwed when passive diffusin slwed (active transprt, enzyme mediated functins nt altered) Duratin f actin can be extended Unbund drug cncentratin can be affected by ther drugs that bind prteins with higher affinity (displaced) Unless explicitly stated plasma cncentratins are a measure f bund and unbund drug. Lwer Vd, higher cncentratin in ttal plasma, but lwer cncentratin in plasma water. Is it clinically relevant? Article published suggest the rle f plasma-prtein binding is nt as significant in clinical practice as it is in lab thery Open system with eliminatin f unbund drug 5% increase f unbund drug distributes thrughut bdy vlume As unbund drug cncentratin increases, rate f eliminatin increases Plasma prtein binding mst imprtant When drug A is displaced by drug B When Drug A has a narrw TI Drug Tissue Binding Extravascular prtein reservir (bind t prtein utside plasma) Lwer cncentratin in plasma, therefre higher Vd Prlngs duratin f actin r t ½ Drugs binding t cytplasmic prteins Lwers plasma cncentratin, therefre increases Vd Many anti-bacterials Quinlnes, flurquinne Lead (replaces Ca++ at many sites in bnd frmatin) Methtrexate Many drugs targets are intracellular prteins Anticancer Might be respnsible fr txicity assciated with sme drugs

5 FAT as a reservir Chrnic expsure t lipid-sluble drugs can cause accumulatin Lwer plasma cncentratin, therefre increases Vd Lwer perfusin rate, therefre increased time t equilibrate between plasma and fat. Increased time t accumulate, increased time fr remval Can increase duratin f actin Can act as strage site May result in acute pisning (DDT) Examples: Diazepm, THC, chlrinated hydrcarbns, thipental readily assciate with adipse Adipse pr circulatin, takes lng time t reach adipse, remve frm adipse. Enterhepatic Circulatin Drugs may mre may nt betransfrmed in cycle Drugs recycle therefre lwers plasma cncentratin and increases Vd Prlng duratin f actin Examples: Imipramine, Mrphine A nte n drug residues in fd animals Drug reservirs and sites f prlnged sequestratin is a majr cncern in fd animals. Residues an be fund in muscle, milk, eggs, liver, etc. Many drugs are nt apprved fr use in fd animals. Drug will nt be apprved fr use in milking dairy cattle if drug residues can be detected fr lnger than 96 hurs in milk. Other factrs affecting drug distributin Bld flw heart, lungs, liver, kidney, brain PH trapping inside cells Disease: Edema increases water, affects Vd The rate at which a drug is released frm a reservir is gverned by the same factrs as thse described fr its distributin Reservirs can be useful in achieving a prlnged effect with an therwise shrt acting drug Reservirs extent t ½ Mre drug may be required t reach therapeutic cncentratins Redistributin IV dse drug in small vlume f bld will mve thrugh pulmnary y and then systemic circuit Cncentratin decreases as drug mixes with larger bld vlume Frm capillaries, drug mves int ECF and equilibrated ~15 minutes Perfusin f different rgans )at rest vs. during exercise)

6 Due t differences in tissue perfusin rates, drugs reach equilibrium in sme tissues faster than thers. In Halethane, exercise reduces bld flw at GI tract 3 types f tissues (depends n amunt f bld flw) Rapid uptake phase: liver, brain, heart Vessel rich grup (VRG) Intermediate phase uptake: muscles Muscle Grup (MG) Slw phase: fat, skin, bne, ligament, teeth, hair Vessel pr grup (VPG), ptentially acts as reservirs When drug administratin stps remval f drug in 3 phases prprtinal t distributin rates. VRG mves ut fast. The vessel rich grup (VRG) tissues are mre ften target fr drug therapy Very rapid nset but within tissue, redistributin time may vary. e.g. gray matter perfusin 4 x greater than white matter Redistributin ccurs t t differences in time-curse f perfusin VRG rapid distributin and clearance In General Oral absrptin and distributin takes ~2hrs Digitxin takes up t 6 hrs after last dse t distribute, binds t muscle Lithium takes clse t 24 hrs (charged mlecule) Aminglycsides (gentamycin) are quite rapid 1h3 Bld sample at half way pint f dsing interval will clsely apprximate stead state cncentratin (based n Absrptin, distributin, and clearance) In Summary Vlume f distributin can be calculated Vd = D/C and represents the vlume that a drug is distributed Vd prvides infrmatin t calculate dsing TBW, plasma, ECF, ther Vs~plasma cmpartment (4% Distributin/Eliminatin will be affected by bld flw

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