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Toxicokinetics is not rocket science. Kent R. Olson, MD Medical Director, SF Division California Poison Control System. . . . a stepwise approach to complicate simple kinetics concepts and freak out fellows. Dr. Bart’s blackboard fun™ presents. Kinetics for DUMMIES ! 1. Absorption
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Toxicokinetics is not rocket science Kent R. Olson, MD Medical Director, SF Division California Poison Control System
. . . a stepwise approach to complicate simple kinetics concepts and freak out fellows
Dr. Bart’s blackboard fun™ presents ... Kinetics for DUMMIES ! 1. Absorption 2. Distribution 3. Elimination
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?
“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
“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)
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
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
Other absorption issues: • Delayed or altered absorption • Massive OD • GI motility altered by drug effect • Anticholinergics • Opioids • Solubility • Modified-release preparations
Modified-release preparation
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
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
Vd for some common drugs Large Vd: • camphor • antidepressants • digoxin • opioids • phencyclidine • phenothiazines Small Vd: • alcohols • lithium • phenobarbital • phenytoin • salicylate • valproic acid
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) ??
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
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
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
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?
C’ Cnormal binding = P’ Pnormal (1 – fu) + fu fu = fraction unbound
5 mg/L Cnormal binding = 2.2 4.4 (1 – 0.1)+ 0.1
5 mg/L Cnormal binding = = 9.09 mg/L 0.55
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
Effect of saturated Pr binding Plasma protein bound drug Drug in tissues Free drug Drug in tissues Plasma proteins SATURATED Free drug
pH and Vd
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
Remember Henderson-Hasselbalch? Log = pKa – pH OR . . . protonated species unprotonated species protonated/unprotonated = 10pKa-pH
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 ?
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
Dose was 150 mg IV . . . Vd = ? Cp at t = 0 ~ 7.5 mg/L Vd = dose / Cp = 150 / 7.5 = 20 L
Elimination: Can you say “haff-life”?
Half-life = the time it takes for the Cp to drop in half 1 half-life 2 half-lives
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%
Slope = the proportionof drug elimination per unit time (natural log graph) K = slope of
What is Clearance? (Cl) VOLUME per unit TIME cleared of the drug units =mL/minorL/hr
Clearance calculation: • If the reported Cl is 200 mL/min, What is the Half-life? How much drug is gone after 2 hours?
“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
Now try again: • Cl is 200 mL/min • Drug concentration is 1000 ng/mL
Cl x Cp = 200 mL/min x 1000 ng/mL = 200,000 ng/min = 200 mcg/min = 0.2 milligrams/minute !
What is the relationship between Cl and Vd? Slope = Cl Vd 0.693 Vd t 1/2 = Cl
First-order kinetics a.k.a. “concentration-dependent” kinetics Elimination is LINEAR when plotted on semi-log graph
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