Toxicokinetics is not rocket science

1. Toxicokinetics is not rocket science Kent R. Olson, MD Medical Director, SF Division California Poison Control System

2. . . . a stepwise approach to complicate simple kinetics concepts and freak out fellows

3. Dr. Bart’s blackboard fun™ presents ... Kinetics for DUMMIES ! 1. Absorption 2. Distribution 3. Elimination

4. Case 1 • Biff says he drank “2 beers” • His serum ethanol = 0.28 gm/dL • Possible Questions: • How big is Biff? • How big are his beers? • How honest is Biff about his beers?

5. “2 beers” = ? EtOH • Assume: • Pint-sized: 500 mL each • 6.8% EtOH v/v • EtOH ~ 0.7 g/mL Calculation: 1000mL x 6.8mL EtOH/100mL beer x 0.7 g/mL = 47.6 g EtOH

6. Absorption

7. “First-pass effect” • Removal of drug after ingestion, by: • Enzymes in the gut wall • Uptake by the liver • Vomiting, AC, WBI, etc • Ethanol: first-pass removal ~ 6-7% Biff’s absorbed dose: down to 44.5 g (47.6 x 93.5% = 44.5)

8. EtOH FP effect modified by: • Gastric emptying time • Food • Medications (eg, Reglan, ranitidine) • Gender • Age • Most rapid and complete EtOH absorption: • older • female • empty stomach • on metoclopramide

9. Some drugs w/ high FP effecta.k.a. “low bioavailability” • Propranolol • Cyclosporine • Morphine • Desipramine & other TCAs • Implications: • FP removal can be saturated in an OD • Greater proportion of drug will reach the systemic circulation

10. Other absorption issues: • Delayed or altered absorption • Massive OD • GI motility altered by drug effect • Anticholinergics • Opioids • Solubility • Modified-release preparations

11. Modified-release preparation

12. Tylenol “Extended Relief” ingestion Serum APAP level APAP (mg/L) Prob. Toxic Poss. Toxic hrs Note: co-ingestion of Nyquil plus up to 44 g Tylenol ER Ref: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510

13. Volume of Distribution (Vd) • Where the drug goes • Vd = = mg/kg / mg/L = L/kg • Total body water = 0.7 L/kg or ~ 50 L • ECF = 0.25 L/kg or about 15 L in adult • Plasma = 0.07 L/kg or ~ 5 L • For EtOH: Vd ~ 0.7 L/kg amount in body Cp

14. Vd for some common drugs Large Vd: • camphor • antidepressants • digoxin • opioids • phencyclidine • phenothiazines Small Vd: • alcohols • lithium • phenobarbital • phenytoin • salicylate • valproic acid

15. Back to Biff’s beers . . . • How big is Biff?If Vd = amount in body, then Cp0.7 L/kg x Biff (kg) = 44.5 g 0.28 g/dLand Biff = 22.7 kg (50 lb) ??

16. Practice Question: • Boff ingested the contents of his mother’s old Rx of theophylline • What is the highest possible serum concentration he could achieve? • Boff weighs 80 kg • Vd theophylline 0.5 L/kg • Bottle had # 20 pills 300 mg Theo-Dur

17. Cp = dose / Vd Max dose = 20 x 300 = 6000 mg Vd = 0.5 L/kg x 80 kg= 40 L Max Cp = 6000 mg = 150 mg/L 40 L

18. Try this on your own: How many vials of Digoxin-Fab would be needed to neutralize a digoxin serum concentration of 4 ng/mL? (assuming equilibrium) • Vd = 6 L/kg • 50 kg elderly woman • Each vial binds ~ 0.5 mg digoxin

19. Question: • Joe has a serum phenytoin level of 10 mg/L w/ serum albumin 4.4 gm/dL • Josette has a serum phenytoin level of 5 mg/L w/ albumin 2.2 gm/dL • What do they have in common?

20. Protein binding

22. C’ Cnormal binding = P’ Pnormal (1 – fu) + fu fu = fraction unbound

23. 5 mg/L Cnormal binding = 2.2 4.4 (1 – 0.1)+ 0.1

24. 5 mg/L Cnormal binding = = 9.09 mg/L 0.55

25. Some drugs w/ high Pr binding • Carbamazepine fu = 0.2 • Phenytoin 0.1 • Salicylic acid 0.16 • Valproic acid 0.15 • Warfarin 0.03 • Note: Pr binding can be saturated in OD, resulting in greater free fraction

26. Effect of saturated Pr binding Plasma protein bound drug Drug in tissues Free drug Drug in tissues Plasma proteins SATURATED Free drug

27. Salicylate: increasing Vd with incr. dose

28. pH and Vd

29. Salicylate is a Weak Acid (pKa 3.5) TISSUES (pH 6.8) BLOOD (pH 7.4) URINE (pH variable) SH SH SH H+ +S- H++S- H+ + S- Acidosis Alkalosis

30. Remember Henderson-Hasselbalch? Log = pKa – pH OR . . . protonated species unprotonated species protonated/unprotonated = 10pKa-pH

31. Question: • What is the proportion of salicylate in the non-ionized (protonated) state compared with the ionized (non-protonated) state in urine with: • pH = 3.5 ? • pH = 7.5 ?

32. Answer: • pH 3.5 Protonated / nonprotonated = 103.5-3.5 Salicylic acid / salicylate = 100 = 1 Ratio = 1:1 • pH 7.5 Protonated / nonprotonated = 103.5-7.5 Salicylic acid / salicylate = 10-4 Ratio = 1:10,000

33. Dose was 150 mg IV . . . Vd = ?

34. Dose was 150 mg IV . . . Vd = ? Cp at t = 0 ~ 7.5 mg/L Vd = dose / Cp = 150 / 7.5 = 20 L

36. Digoxin OD in a child

38. Lithium

39. Elimination: Can you say “haff-life”?

40. Half-life = the time it takes for the Cp to drop in half 1 half-life 2 half-lives

41. No. of half-lives Increment Percent of maximum 1 50% 50% 2 25% 75% 3 12.5% 87.5% 4 6.25% 93.75% 5 3.125% 96.875% 6 1.5625% 98.4375%

42. Slope = the proportionof drug elimination per unit time (natural log graph) K = slope of

43. What is Clearance? (Cl) VOLUME per unit TIME cleared of the drug units =mL/minorL/hr

44. Clearance calculation: • If the reported Cl is 200 mL/min, What is the Half-life? How much drug is gone after 2 hours?

45. “They reported the CLEARANCE was really good - - - 200 mL/min . . .” • But, Cl is expressed in mL/min . . .(NOT mg/min or gm/hr or tons/day) • Total drug elimination depends on drug concentration:mcg/mL x mL/min = mg/min

46. Now try again: • Cl is 200 mL/min • Drug concentration is 1000 ng/mL

47. Cl x Cp = 200 mL/min x 1000 ng/mL = 200,000 ng/min = 200 mcg/min = 0.2 milligrams/minute !

48. What is the relationship between Cl and Vd? Slope = Cl Vd 0.693 Vd t 1/2 = Cl

49. First-order kinetics a.k.a. “concentration-dependent” kinetics Elimination is LINEAR when plotted on semi-log graph

50. What happens in OD? • Saturation of normal routes of elimination  “zero-order kinetics” First-order Half-life = 1 hour Hours Level 00:00 60 01:00 30 02:00 15 03:00 7.5 Zero-order Elim. = 30 mg/L/hr Hours Level 00:00 210 01:00 180 02:00 150 03:00 120