Toxicokinetics 4042019

toxicokinetics

2. Definition
•Toxicokineticsdescribestherateof
achemicalenterthebodyandhow
thecompoundmetaboliseand
excreteonceitisinthebody.
•Simply,howasubstancegetsintothe
bodyandwhathappenstoitinthe
body.

3. •Toxicokineticsdealswithwhatthebodydoes
withadrugwhengivenarelatively
highdoserelativetothetherapeuticdose.
•Thescienceoftoxicologyhasevolvedto
include environmental and
occupationalchemicalsaswellasdrugs.
•Toxicokineticsisthustheappropriatetermfor
thestudyofthekineticsofallsubstancesat
toxicdose/exposurelevels.

4. someexamplesofhowtoxicokineticsof
asubstancecaninfluenceitstoxicity:
•Absorption—A highlytoxic substancethat is poorly
absorbed may be no more hazardous than asubstanceof
lowtoxicitythat is highly absorbed.
•Biotransformation— Two substanceswith
equaltoxicityandabsorptionmaydifferinhowhazardous
theyaredependingonthenatureof
theirbiotransformation.Asubstancethatisbiotransformed
intoamoretoxicmetabolite(bioactivated)isa
greaterhazardthanasubstancethatisbiotransformedinto
alesstoxicmetabolite(detoxified).

5. Difference between pharmacokinetics
and toxicokinetics
Pharmacokinetics
•It has been with us for many
years.
•Extensive collaboration with
pharmacology.
•Lower doses than
toxicokinetics
Toxicokinetics
•It is a far more recent
discipline.
•It need extensive
collaboration with
toxicologist,toxicokinetics
andpharmacokinetics.
•Muchhigherdosesareused

6. Four processes are involved
intoxicokinetics:
•Absorption—thesubstanceenters the body.
•Distribution—thesubstancemoves from the
site of entry to other areas of the body.
•Biotransformation—the body changes
(transforms) thesubstanceinto
newchemicals(metabolites).
•Excretion—thesubstanceor
itsmetabolitesleave the body.

7. Absorption,distribution,biotransformation,
andeliminationare inter-related processes as
illustrated in Figure

8. •Theabilitytobeabsorbedisessentialfor
systemictoxicitytooccur.
•Somechemicalsarereadilyabsorbedand
otherspoorlyabsorbed.
•Forexample,nearlyallalcoholsare
readilyabsorbedwheningested,whereas
thereisvirtuallynoabsorptionformost
polymers.

9. Absorption
•Thekeyfactorinthequantitativeassessment
ofhumanhealthriskfromchemicalexposure
isthecorrectquantificationoftheamountof
thechemicalsubstancepassingthroughthe
bio-membrane(i.e,skin)andthusactually
enteringthebody.
•WithouttheTKstudy,usually100%
absorptionisassumed,whichmayover-
predicttherisksofsystematictoxicity.

10. Distribution
Thedistributionoftoxicantsandtoxic
metabolitesthroughoutthebody
ultimatelydeterminesthesiteswhere
toxicityoccurs.
Amajordeterminantofwhetherornota
toxicantwilldamagecellsisitslipid
solubility.
Ifatoxicantislipid-solubleitreadily
penetratescellmembranes.

11. Many toxicants are stored in the body.
Fat tissue, liver, kidney, and bone are
the most common storage depots.
Blood serves as the main avenue for
distribution.
Lymph also distributes some
materials.

12. Metabolism
•Metabolism, also known
asbiotransformation,isamajorfactorin
determiningtoxicity.
•Theproductsofmetabolismareknown
asmetabolites.
•Therearetwotypesofmetabolism-
1.Detoxification
2.Bioactivation.

13. •Detoxificationistheprocessbywhicha
xenobioticisconvertedtoalesstoxicform.
Thisisanaturaldefensemechanismofthe
organism.Generallythedetoxificationprocess
convertslipid-solublecompoundstopolar
compounds.
•Bioactivationistheprocessbywhicha
xenobioticmaybeconvertedtomorereactive
ortoxicforms.

14. Excretion
Thesiteandrateofexcretionisanother
majorfactoraffectingthetoxicityofa
substance.
Thekidneyistheprimaryexcretoryorgan,
followedbythegastrointestinaltract,and
thelungs(forgases).
Substancesandmetabolitesmayalsobe
excretedinsweat,tears,andmilk.

15. Excretion
•Alargevolumeofbloodserumisfiltered
throughthekidney.
•Lipid-solubletoxicantsarereabsorbed
andconcentratedinkidneycells.
•Impairedkidneyfunctioncausesslower
eliminationoftoxicantsandincreases
theirtoxicpotential

16. •Toxicokineticsmaythusbe
differentfrompharmacokinetics,
fromatechnologicalperspective,
inmanyways.
•Solubility
•Stability

17. Solubility:
Inviewoftheveryhighdosesusedin
toxicokinetics,onecanreadilyencountersolubility
problems.
Thesemayoccurduringdosageformpreparation
andadministrationandalsointermsofdrug
solubilityinthegastrointestinal(GI)tract.
Moreseriously,perhaps,thiscouldgiverisetodrug
precipitationinbiologicalfluidsandinorgansand
tissuesgivingrisetotoxicitythatmaynotbe
associatedwiththeintrinsicpharmacologicalor
toxicologicaleffectsofthedrug.

18. Stability
Compoundstabilitymaybeinfluencedby
concentrationsandamountsofsubstancesusedin
toxicology.
Traditionally,intoxicologyandtoxicokineticstudies,
drugsmaybeadministeredmixedwithfeed,and
thisisrealisticintermsofresources.
Dosingcompoundsintoxicologystudiesbygavage
dosesislabor-intensiveandexpensive.
However,finedispersionofdrugwithfeed,with
possiblestorageoverconsiderableperiodsinthis
finelydispersedform,cangiverisetodrug
degradationproblems.