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1. Drug Elimination and
Renal Clearance

2. LEARNING OUTCOMES
•Describe the main routes of drug elimination from the body
•Understand the importance of the role of clearance as a PK parameter.
•Define clearance and its relationship to a corresponding half-life and a volume of distribution.
•Differentiate between clearance and renal clearance.
•Describe the processes for renal drug excretion and explain which renal excretion process predominates in the
kidney for a specific drug, given its renal clearance.
•Understand anatomy of kidney
•Define renal Plasma Flow, to understand its formula and its normal value
•Describe the renal clearance model based on renal blood flow, glomerular filtration, secretion and drug
reabsorption.
•Derive equation for fraction of Ionized drug (For weakly acidic and basic drugs)
•Understand U/P ratio for weakly acidic and basic drug
•Understand the effect of urine pH on drug reabsorption
•Interpret factors affecting renal excretion
•Describe organ drug clearance in terms of blood flow and extraction.
•Calculate clearance using different methods including the physiological, noncompartmental, and
compartmental approaches
•Solve numericals of chapter renal excretion of drugs

3. Drug Elimination
•Drugeliminationreferstotheirreversibleremovalofdrug
fromthebodybyallroutesofelimination.
•Drugeliminationisusuallydividedintotwomajor
components:excretionandbiotransformation.

4. Drug Elimination
•Drugexcretionistheremovaloftheintactdrug.
•Nonvolatiledrugsareexcretedmainlybyrenalexcretion
•Otherpathwaysfordrugexcretionmayincludetheexcretion
ofdrugintobile,sweat,saliva,milk(vialactation),orother
bodyfluids.
•Volatiledrugs,suchasgaseousanestheticsordrugswithhigh
volatility,areexcretedviathelungsintoexpiredair.

5. Drug Elimination
•Biotransformationordrugmetabolismistheprocessbywhich
thedrugischemicallyconvertedinthebodytoametabolite.
•Biotransformationisusuallyanenzymaticprocessandthe
enzymesarelocatedintheliver.
•Afewdrugsmayalsobechangedchemicallybyanon-enzymatic
process(eg,esterhydrolysis).

6. Drug Elimination
•Clearancemaybedefinedasthevolumeoffluidclearedof
drugfromthebodyperunitoftime.
•Theunitsforclearancearemillilitersperminute(mL/min)or
litersperhour(L/hr).
•Inaddition,forfirst–ordereliminationprocesses,clearanceisa
constant,whereasdrugeliminationrateisnotconstant.

7. The Kidney
•Theliverandkidneyarethetwomajordrugeliminationorgans
inthebody.

8. The Kidney
•Functionsofthekidney:
1.Removalofmetabolicwasteproducts
2.Maintainsaltandwaterbalance
3.Secretionofrenin,whichregulates
bloodpressure
4.Secretionoferythropoietin,which
stimulatesredbloodcellproduction.

9. Anatomy of Kidney
•Thekidneysarelocatedinthe
peritonealcavity.
•Theouterzoneofthekidneyis
calledthecortex,andtheinner
regioniscalledthemedulla.
•Thenephronsarethebasic
functionalunits,collectively
responsiblefortheremovalof
metabolicwasteandthe
maintenanceofwaterand
electrolytebalance.

10. Anatomy of Kidney
•Eachkidneycontains1to1.5millionnephrons.
•Theglomerulusofeachnephronstartsinthecortex.
•CorticalnephronshaveshortloopsofHenlethatremain
exclusivelyinthecortex;juxtamedullarynephronshavelong
loopsofHenlethatextendintothemedulla.
•ThelongerloopsofHenleallowforagreaterabilityofthe
nephrontoreabsorbwater,therebyproducingamore
concentratedurine.

11. Anatomy of Kidney

12. Anatomy of Kidney

13. Blood Supply
•Therenalbloodflow(RBF)isthevolumeofbloodflowing
throughtherenalvasculatureperunittime.
•Renalbloodflowexceeds1.2L/minor1700L/day.
•Renalplasmaflow(RPF)istherenalbloodflowminusthe
volumeofredbloodcellspresent.
•Renalplasmaflowisanimportantfactorintherateofdrug
filtrationattheglomerulus.

14. Blood Supply
RPF = RBF –(RBF X Hct)
where Hct is hematocrit.
•Hctisthefractionofbloodcellsintheblood,about45%ofthetotal
bloodvolume,or0.45.
•Therelationshipofrenalbloodflowtorenalplasmaflowisgivenbya
rearrangementof
RPF = RBF (1-Hct)
Assumingahematocritof0.45andaRBFof1.2L/min,usingtheabove
equation,
RPF=1.2–(1.2x0.45)=0.66L/minor660mL/min,approximately950
L/day.

15. Blood Supply
•Theglomerularfiltrationrate(GFR)isabout125mL/mininan
averageadult,orabout20%oftheRPF.
•TheratioGFR/RPFisthefiltrationfraction.

16. Glomerular Filtration and Urine
Formation
•AnormaladultmalesubjecthasaGFRofapproximately125
mL/min.
•About180Loffluidperdayarefilteredthroughthekidneys.
•Inspiteofthislargefiltrationvolume,theaverageurinevolumeis
1–1.5L.
•Upto99%ofthefluidvolumefilteredattheglomerulusis
reabsorbed.Besidesfluidregulation,thekidneyalsoregulatesthe
retentionorexcretionofvarioussolutesandelectrolytes.
•Withtheexceptionofproteinsandprotein-boundsubstances,
mostsmallmoleculesarefilteredthroughtheglomerulusfromthe
plasma.

17. Renal Excretion of drugs
⚫The most important organ for drug excretion is the kidney.
The principal processes that determine the
urinary excretion of drugs are:
–Glomerular filtration.
–Active tubular secretion.
–Passive or active tubular re-absorption.

19. ⚫Driving force for GF is hydrostatic pressure of blood
flowing in capillaries.
⚫Hydrostatic pressure pushes a portion of blood to be
filtered across a semi-permeable membrane into the
Bowman’s Capsule.
⚫Most drugs are filtered through glomerulus.
⚫Blood cells, platelets, and plasma proteins are retained in
the blood and not filtered.
Glomerular filtration (GF)

21. Active Tubular Secretion of drugs
•occurs mainly in proximal tubules
•It increases drug concentration in filtrate
•Drugs undergo active secretion have
excretion rate values greater than normal
GFR
•Secretion of K
+
, H
+
, ammonia; excess
amino acids
•Secretion of ionized drugs into the lumen
e.g. penicillin

22. Characters of active tubular secretion:
•Is an active process
•needs energy
•requires carriers (transporters)
•can transport drugs against concentration
gradients
•Saturable
•Not specific (competition may happens)

24. Two secretion mechanisms are identified
System for secretion of organic
acids/anions
⮚Penicillin, salicylates, sulfonamides
⮚Probenecid, uric acid
Systemfororganicbases/cations
⮚Atropine, morphine
⮚Catecholamines, quinine,
neostigmine

25. Tubular re-absorption
•After glomerular filtration, drugs may be
reabsorbed from tubular lumen into
systemic circulation.
•It takes place all along the renal tubules.
•Drugs undergo tubular re-absorption have
excretion rates less than the GFR. e.g.
Glucose
•Re-absorption increases half life of a drug.
•Re-absorption may be active or passive.

27. Active tubular re-
absorption
•It occurs with endogenous
substances or nutrients that
the body needs to conserve.
e.g. glucose, electrolytes,
amino acids, uric acid,
vitamins.
•Probenecidacts as a
uricosuric agentin treatment
of gout.
•It increases excretion of uric
acid in urine by inhibiting
active tubular re-absorption
of the endogenous metabolite
uric acid.

29. Passive Tubular re-absorption and urinary pH trapping
(Ion trapping)
•Most drugs are weak acids or weak bases thus by
changing pH of urine via chemicals can inhibit the
passive tubular re-absorption of drugs.
•Urine is normally slightly acidic and favors
excretion of basic drugs.

31. Renal Drug Excretion
For a weak acid drug, the Henderson–Hasselbalch equation is given as

32. Renal Drug Excretion
•ForacidicdrugswithpK
avaluesfrom3to8,achangein
urinarypHaffectstheextentofdissociation.
•Theextentofdissociationismoregreatlyaffectedbychanges
inurinarypHfordrugswithapK
aof5thanwithapK
aof3.
•WeakacidswithpK
avaluesoflessthan2arehighlyionizedat
allurinarypHvaluesandareonlyslightlyaffectedbypH
variations.

33. Renal Drug Excretion
•ThegreatesteffectofurinarypHonreabsorptionoccurswith
weakbasedrugswithpK
avaluesof7.5–10.5.
•FromtheHenderson–Hesselbalchrelationship,aconcentration
ratioforthedistributionofaweakacidorbasicdrugbetween
urineandplasmamaybederived.
•Theurine–plasma(U/P)ratiosforthesedrugsareasfollows.

34. Renal Drug Excretion

35. Renal Drug Excretion
•Forexample,amphetamine,aweakbase,willbereabsorbedifthe
urinepHismadealkalineandmorelipid-solublenonionizedspecies
areformed.
•Incontrast,acidificationoftheurinewillcausetheamphetamineto
becomemoreionized(formasalt).
•Thesaltformismorewatersolubleandlesslikelytobereabsorbedand
hasatendencytobeexcretedintotheurinemorequickly.
•Inthecaseofweakacids(suchassalicylicacid),acidificationofthe
urinecausesgreaterreabsorptionofthedrugandalkalinizationofthe
urinecausesmorerapidexcretionofthedrug.

36. •Bothsulfisoxazole(Gantrisin)tabletsandthecombinationproduct,
sulfamethoxazole/trimethoprim(Bactrim)tablets,areusedforurinary
tractinfections.
•Sulfisoxazoleandsulfamethoxazolearesulfonamidesthatarewell
absorbedafteroraladministrationandareexcretedinhighconcentrations
intheurine.
•SulfonamidesareN-acetylatedtoalesswater-solublemetabolite.Both
sulfonamidesandtheircorrespondingN-acetylatedmetaboliteareless
watersolubleinacidandmoresolubleinalkalineconditions.
•Inacidurine,renaltoxicitycanoccurduetoprecipitationofthe
sulfonamidesintherenaltubules.
•Topreventcrystalluriaandrenalcomplications,patientsareinstructedto
takethesedrugswithahighamountoffluidintakeandtokeeptheurine
alkaline.

37. Let pKa = 5 for an acidic drug. Compare the U/P at
urinary pH (a) 3, (b) 5, and (c) 7.

38. •InadditiontothepHoftheurine,therateofurineflowinfluences
theamountoffiltereddrugthatisreabsorbed.
•Thenormalflowofurineisapproximately1-2mL/min.
•Nonpolarandnonionizeddrugs,whicharenormallywell
reabsorbedintherenaltubules,aresensitivetochangesintherate
ofurineflow.
•Drugsthatincreaseurineflow,suchasethanol,largefluidintake,
andmethylxanthines(suchascaffeineortheophylline),decrease
thetimefordrugreabsorptionandpromotetheirexcretion.
•Thus,forceddiuresisthroughtheuseofdiureticsmaybeauseful
adjunctforremovingexcessivedruginanintoxicatedpatient,by
increasingrenaldrugexcretion.

39. Factors affecting renal excretion of drug
⮚Physiochemical properties of drugs
•Molecular weight
•Lipid solubility
•Volume of distribution
•Binding character
•Degree of ionization
⮚Blood flow to the kidney
⮚Urine pH
⮚Biological factor e.g. age
⮚Disease states

40. Factors affecting renal excretion
Drug MW (Molecular Weight):larger MW drugs are difficult to be
excreted than smaller MW especially by glomerular filtration.
Drug lipid solubility:urinary excretion is inversely related to lipophilicity,
increased lipid solubility increase volume of distribution of drug and
decrease renal excretion.
Volume of distribution: Renalclearance is inversely related to volume of
distribution of drugs (Vd). A drug with large Vd is poorly excreted in urine.

41. Factors affecting renal excretion
Renalbloodflow:increasedperfusionleadstoincreasedexcretion;
Importantfordrugsexcretedbyglomerularfiltration.
Binding characteristics of the drugs
Drugsthatareboundtoplasmaproteinsbehaveasmacromoleculesand
cannotbefilteredthroughglomerulus.Onlyunboundorfreedrugappear
inglomerularfiltrate.Proteinbounddrughaslonghalflives.

42. Factors affecting renal excretion
Biological factor:Age can affect renal clearance. Renal clearance is
reduced in neonates and elderly.
Disease statesimpairs the elimination of drugs e.g. hypertension,
Diabetes, pyelonephritis

43. Drug Clearance
•Drugclearanceisapharmacokinetictermfordescribingdrug
eliminationfromthebodywithoutidentifyingthemechanismof
theprocess.
•Drugclearance(bodyclearance,totalbodyclearance,orCl
T)
considerstheentirebodyasasingledrug-eliminatingsystemfrom
whichmanyunidentifiedeliminationprocessesmayoccur.
•Drugclearanceisdescribedintermsofvolumeoffluidclearof
drugpertimeunit(eg,mL/min).
•Justastheeliminationrateconstant(k)representsthesumtotal
ofalltherateconstantsfordrugelimination,includingexcretion
andbiotransformation,Cl
Tisthesumtotalofalltheclearance
processesinthebody,includingclearancethroughthekidney
(renalclearance),lung,andliver(hepaticclearance).

44. Drug Clearance

45. Clearance Models
•ThecalculationofclearancefromkandV
Dassumes
(sometimesincorrectly)adefinedmodel,whereasclearance
estimateddirectlyfromtheplasmadrugconcentrationtime
curvedoesnotassumeanymodel.

46. Physiologic/Organ Clearance
•Clearancemaybecalculatedforanyorgan
involvedintheirreversibleremovalofdrugfrom
thebody.
•Manyorgansinthebodyhavethecapacityfor
drugelimination,includingdrugexcretionand
biotransformation.
•Thekidneysandliverarethemostcommon
organsinvolvedinexcretionandmetabolism,
respectively.
•Physiologicpharmacokineticmodelsarebasedon
drugclearancethroughindividualorgansor
tissuegroups

47. Drugclearancemodel.(Q=bloodflow,C
a=
incomingdrugconcentration[usuallyarterial
drugconcentration],C
v=outgoingdrug
concentration[venousdrugconcentration]).

48. Physiologic/Organ Clearance
•Foranyorgan,clearancemaybedefinedas
thefractionofbloodvolumecontainingdrug
thatflowsthroughtheorganandiseliminated
ofdrugperunittime.
•Fromthisdefinition,clearanceistheproduct
ofthebloodflow(Q)totheorgan,andthe
extractionratio(ER).
•TheERisthefractionofdrugextractedbythe
organasdrugpassesthrough.

49. Physiologic/Organ Clearance
•Clearance = Q (ER)
•Ifthedrugconcentrationintheblood(C
a)
enteringtheorganisgreaterthanthedrug
concentrationofblood(C
v)leavingtheorgan,
thensomeofthedrughasbeenextractedbythe
organ.
•TheERisC
a–C
vdividedbytheenteringdrug
concentration(C
a),asshown
ER = C
a-C
v
C
a

50. Physiologic/Organ Clearance
•ERisaratiowithnounits.ThevalueofERmayrangefrom0
(nodrugremovedbytheorgan)to1(100%ofthedrugis
removedbytheorgan).
•AnERof0.25indicatesthat25%oftheincomingdrug
concentrationisremovedbytheorganasthedrugpasses
through.

51. Physiologic/Organ Clearance
•Substituting for ER into Equation for clearance we
get
Cl = Q (C
a-C
v)
C
a
•Thephysiologicapproachtoclearanceshowsthat
clearancedependsonthebloodflowrateand
theabilityoftheorgantoeliminatedrug,
whereastheclassicaldefinitionsofclearanceis
thataconstantorstaticfractionofthevolumein
whichthedrugiscontainedisremovedperunit
timebytheorgan.

52. General approaches to clearance

53. Drug renal clearance:
▪If renal clearance is impaired, this may increase
t ½ of drugs and toxic levels of drugs may remain in the
body.
▪Renal clearance is especially important for some drugs
which are:
▪Mainly excreted by the kidney
▪Have narrow therapeutic index (e.g. lithium, digoxin,
warfarin).

54. Diseases that can decrease renal clearance
–Reduced renal blood flow
•Congestive heart failure.
•Hemorrhage
•Cardiogenic shock
–Decreased renal excretion :
•Renal disease (e.g. glomerulonephritis).
This may increase half-life (t ½ ) of drugs

55. So what should we do in renal impairment?
•Dose reduction of drugs is required (when
creatinine clearance is below 60 ml/min).
–keep the usual dose but prolong the dosing
intervals (e.g. gentamicin)
–decrease the dose without changing dosing
intervals (e.g. digoxin)
•Monitor blood levels of drugs (therapeutic drug
monitoring).

56. Dose reduction in renal impairment
Antibiotics:
–Penicillins, cephalosporins
–Aminoglycosides (gentamycin)
–Sulfonamides
❑Non steroidal anti-inflammatory drugs
(NSAIDs)
❑Lithium
❑Digoxin
❑Immunosuppressants(cyclosporine)
❑Anticancer drugs(cisplatin -cyclophosphamide)
These drugs are contraindicated in:
Renal failure –Elderly patients

57. When dose reduction is not required in renal
impairment ?
⮚Few drugs e.g. ceftriaxone, minocycline that are
excreted into feces (biliary excretion) doesn’t
need dose adjustment in renal impairment.

58. Comparison of Drug Excretion
Methods

59. Comparison of Drug Excretion Methods
•Theactualrenalclearanceofadrugisnot
generallyobtainedbydirectmeasurement.
•Theclearancevalueforthedrugisoften
comparedtothatofastandardreference,such
asinulin,whichisclearedcompletelythroughthe
kidneybyglomerularfiltrationonly.
•Clearanceratio,whichistheratioofdrug
clearancetoinulinclearance,maygivean
indicationforthemechanismofrenalexcretion
ofthedrug.

60. ComparisonofClearanceofaSample
DrugtoClearanceofaReferenceDrug,
Inulin

61. References
•AppliedBiopharmaceuticsandPharmacokinetics–Leon
Shargel,SussanaWu-Pong,AndrewB.C.Yu,6
th
Edition,Mc
GrawHillInc.
Chapter -6 Page -107 to 127