1. Toxicokinetics 1 Crispin Pierce, Ph.D. University of Washington crispo@u.washington.edu (206) 616-4390

3. Absorption Absorption assumes primary importance in oral, inhalation, and dermal exposures. The two kinetic parameters of concern are the rate of absorption and the extent of absorption (or bioavailability).

4. Rate of Absorption zThe rate of absorption determines the time of onset and the degree of acute toxicity. This is largely because time to peak (Tpeak) and maximum concentration (Cmax) after each exposure depend on the rate of absorption.  Rate the following processes in order of fastest to slowest: ORAL, DERMAL, INHALATION, INTRAVENOUS EXPOSURE.

5. Slowing of absorption (A  B) - prolonged Tp - lower Cmax In instances when the absorption rate is slower than elimination rate, the rate of washout of toxicant becomes rate-limited by absorption rather than by elimination (i.e., a depot effect).

7. ? zHow does having pizza with your beer get you drunk more slowly?

8. Systemic Availability zThe actual extent of exposure as defined by the amount of toxicant reaching the systemic circulation is determined by (1) entry barrier permeability, and (2) the extent of "first-pass" metabolism.

9. zThe fraction of dose reaching the system circulation in intact form, or systemic availability (F), is estimated from either the AUCs, yF = (AUC route /AUC i.v. )  Or from the amount of intact toxicant excreted in urine or exhaled via the lungs (A ex ). yF = (A ex-route /A ex-i.v. )

10. ? zIs mercury amalgam in tooth fillings dangerous?

11. Modeling Absorption yIntravenous dosing xIV rate = IV dose / Time inf x and input into venous blood. yPercutaneous dosing xPerc rate = (Perc dose exp(-K A,perc Time))K A,perc xand input into venous blood

12. yOral dosing xOral rate = (Oral dose exp(-K Aoral Time)) K A oral xand input into liver yInhalation dosing xInhalation rate = C art Q c xQ p * (C inh - C alv ) = Q c * (C art - C ven ) xk blood/air = P blood/air = C art / C alv xC art = (Q p P b/a C inh + C ven P b/a Q c )/(Q c P b/a + Q p )

13. Volume of Distribution zThe Volume of Distribution is the apparent volume into which a drug or toxicant distributes, and provides a proportionality constant between blood (or plasma) concentration and the amount in the body: yVolume of Distribution = Amount / Concentration

14. zThe volume of distribution can be readily calculated after an intravenous bolus dose of a substance that exhibits "one-compartment model" characteristics: yVolume of Distribution = Dose / Initial Concentration

15. zHowever, because of the uncertainty in the estimate of Co, volume can be more accurately estimated by V = Dose / (kAUC), where AUC is the area under the concentration-time curve.

16. zThe volume of distribution does not necessarily correspond to any physiologic volume, and is influenced by binding to plasma and tissue constituents. Volume can range from about 3 liters (as is seen with Tolbutamide, which is distributed in blood only, to about 50,000 liters (as is seen with Quinacrine, which distributes and binds to many tissues).

17. zThe volume of distribution relates blood conc. to the total body burden of a toxicant, i.e., A Body = VC blood zPhysiologic Meaning? A measure of extravascular distribution. zTwo determinants of distribution into a tissue region: yTissue or organ volume V ti yDistribution or Partition ratio P tissue/blood = C ti /C blood a constant @ pseudo-distribution equilibrium or steady state.

18. zAccordingly, i th Tissue Load = V ti C ti = V ti (P i, C blood ) zTotal Tissue Load =  V ti P i C blood zTotal Body Load = Amount in blood + Amount in tissues zA Body = V blood C blood +  V ti P i C blood = (V blood +  V ti P i )C blood

19. zV = A Body /C blood = V blood +  V ti P i where V blood, V ti and P i are constant. zSince P i can assume a value ~0- , V varies from a minimum of V blood to many times the body size. Because the volume of distribution reflects the degree of xenobiotic dispersal and binding to all tissues, the following relationship is observed:V initial < V steady-state < V terminal phase

20. ? zWould a chemical that is highly soluble in water, such as ethanol, have a large or small volume of distribution? zHow about a chemical that is highly soluble in fat, such as dioxin (TCDD)?

21. Clearance zClearance is a measure of the body's ability to completely clear a drug or toxicant from blood or plasma. Clearance is the rate of elimination by all routes relative to the concentration in a systemic biologic tissue, and is measured in units of flow, or volume per unit time. yCL (units of volume/time) = Rate of elimination (units of mass/time) / Concentration (units of mass/volume)

22. zClearance is normally measured by collecting blood concentration-time data following a known dose, and using the following equation: CL (units of volume/time) = F*Dose (units of mass) / AUC (units of time-mass/volume) where F is the bioavailability (fraction of dose entering systemic circulation), and AUC is the area under the blood concentration- time curve.

23. AUC Time Blood (or plasma) Concentration CL = F·Dose/AUC

24. zClearance also plays a role in determining the steady-state concentration of a drug or toxicant: zC steady-state = Rate of administration/ CL zArea Under the Blood Concentration Time Curve (AUC): an internal or systemic exposure index.

25. z& since C 0 = Dose/V, then AUC = Dose/kV zThe product kV is equal to clearance. zAUC = Dose/CL or CL = Dose/AUC zi.e., clearance governs the extent of systemic exposure as represented by AUC for a given dose of toxicant.

26. Physiologic Basis of Clearance zBlood clearance can be resolved into components representing the various metabolic and excretory pathways of elimination, e.g., CL = CL metabolism + Cl exhalation zor further resolved into organ clearances, e.g., CL = (CL liver + CL g.i. tract + CL kidney + CL lung +...) zIndividual organ clearance can in turn be related to organ blood flow (Q i ) and extraction efficiency (E i ). For instance, Hepatic Clearance (CL liver ) = Q liver E h, note that E h varies from 0–1 (i.e., 0 to 100% extraction)

27. ? zWould rapid breathing increase the clearance of a substance that leaves the body through the breath (such as nitrous oxide used in dentistry)?

28. Half-Life zThe Half-life is a measure of how rapidly a steady-state concentration will be achieved during constant rate dosing, and conversely how rapidly the concentration will fall after cessation of exposure.

29. zHalf-life is related to the elimination rate constant k by the formula: t 1/2 = ln 2 / k zThe elimination rate constant, like the clearance, is a fractional rate of decline: k = Rate of elimination / Amount zSince CL = Rate of elimination/Concentration, the elimination rate constant can be estimated: k = CL / Volume of Distribution

30. zHalf-life can then be found by t 1/2 = ln 2/ k = ln 2 * V / CL zElimination Half-life (t 0.5, t 1/2 ) is a characteristic of First-order kinetics. For a one-compartment model: dA Body = - k A Body z Since A Body declines with time, elimination rate also decreases!

31. zHowever, the fractional rate is a constant, i.e., z - 1 A Body -dA Body /A Body z —— ———  ——————— = k (time -1 ) z A Body dt dt zUpon integration, A Body = A 0 e -kt zA 0 = Body load @ t=0

32. zBut blood conc. rather than body load is measured. zA Body ~ C blood and A Body = VC blood zC blood = C 0 e -kt orLn C blood = Ln C 0 - kt where C 0 =Blood conc. @ t=0 zNote that when C blood = 1/2C 0, t = 0.693/k = t 1/2

33. zIt always takes 1 t 1/2 to reach 50% of any starting conc. (i.e., t 1/2 independent of C 0 ) zTakes about 3-4 t 1/2 s to effect 90% of elimination or to achieve 90% of the steady-state value under constant exposure.

34. zFor compounds with multicompartmental kinetics, there will be a t 1/2 estimate for each of the exponential phases. The terminal t 1/2 is often quoted as the "Elimination t 1/2," whereas the t 1/2 s of the earlier phases are referred to as "Distribution t 1/2 s.” zFor example, in a two compartment model described by C blood = Ae -at + Be -bt, t 1/2,a = 0.693/a and t 1/2,b = 0.693/b

35. ? zHow would half-life be affected if a condition such as kidney failure doubled the volume of distribution for a particular drug? zDoes drinking coffee or another source of caffeine help you to sober up? (Hint: caffeine does not affect the volume of distribution or clearance of ethanol.)

36. zWhy are certain subpopulations (e.g., pregnant women, children) more susceptible to methyl mercury toxicity? (Hint: Might certain populations get higher doses of chemicals, possibly concentrated in smaller masses of tissue?)