5 - Disposition of Toxicants

Question 1

Dose impacted by exposure factors such as…

Answer 1

1. Frequency of exposure
2. Environmental concentration
3. Toxicant properties
4. Exposure routes

Question 2

Standard exposure estimates (especially environmental) are measured in…

Answer 2

parts per million

Question 3

Exposure via respiratory route

Answer 3

It is the most lethal route due to a lack of horny layer and ease of exposure.

Question 4

Lead absorption

Answer 4

Respiratory absorption rate 30-40% (2-3x higher in kids)
GI Absorption 10-15% (40-50% in kids)

Question 5

Predominant effects of lead poisoning of haemopoiesis

Answer 5

1. Pb inhibits heme formation by blocking ferrochelatase
2. Which normally incorporates Fe2+ into protoporphyrin IX to form heme
3. Leads to zinc protoporphyrin biomarker of poisoning

Question 6

How doe solubility effect distribution?

Answer 6

Highly hydrophilic molecules ➔ trapped in blood
Highly lipophilic molecules penetrate deeper into tissues (if they get there)

Question 7

What is AUC

Answer 7

The plasma time curve (= F.Dose/Clearance) how much of a given dose was seen in the blood/plasma

Question 8

What is the F in the AUC equation?

Answer 8

Bioavailability (AUC oral / AUC iv)

Question 8

Why is AUC used in toxicology?

Answer 8

Comparing exposures
* Differences in ADME can be seen through AUC ratios

Question 9

Average concentration can be determined by…

Answer 9

AUC / time

Question 10

Final distribution depends on…

Answer 10

Affinity for various organs, LogP, Mw, protein binding

Question 11

Volume of distribution

Answer 11

Large: distribution to total body H2O or deeper tissues
Small: if distribution to plasma H2O only

Question 12

What does C0 = ?

Answer 12

Dose / Vd

Question 13

Plasma Proteins and binding

Answer 13

ɑ1acid glycoprotein binds cationic drugs
Albumins usually bind to acids (-ve charge)
* Albumins interact with the most xenobiotics

Question 14

Phase I Metabolism

Answer 14

Xenobiotic > Derivative. Non-synthetic reactions. Mostly CYP450 mediated
* Oxidation
* Reduction
* Hydrolysis

Question 15

Phase II Metabolism

Answer 15

Derivative > Conjugate
* Conjugation (methyl/acetylation, glycine)
* Anabolic
* Followed by excretion
* Most conjugates are inactive (there are exceptions)

Question 16

As you increase H2O solubility….

Answer 16

Increases excretion (sweat, faeces, urine)

Question 17

Why are lipid soluble compounds harder to excrete?

Answer 17

Stored in fat (DDT, THC)

Question 18

Methanol toxicity

Answer 18

The oxidative metabolite (formic acid) inhibits cytochrome oxidase (mitochondrial toxin) which is toxic to eyes, brain.

Question 19

Methanol toxicity pathway

Answer 19

Alcohol dehydrogenase (ADH) ➔ formaldehyde

Aldehyde dehydrogenase (ALDH) ➔ formic acid

Question 20

Why are Phase II conjugates safer than Phase I? (Paracetamol)

Answer 20

Phase I product is NAPQI (interfere with cell processes, kills liver cells)

Question 21

Toxic metabolites arent always created by our own enzymes…

Answer 21

Klebsiella sp. In gut microbiota biotransform melamine to cyanuric acid

Question 22

Three main process control urinary excretion:

Answer 22

1. Glomerular filtration
2. Tubular secretion
3. Passive tubular reabsorption

Question 23

Glomerular Filtration

Answer 23

Blood filtered as it reaches kidneys
* Size dependant
* No transporters, no max capacity
* Subject to renal blood flow + perfusion
* GFR ^ with obesity

Question 24

Tubular secretion

Answer 24

**Proximal** tubule * **OAT** (anion) and **OCT** (cation) systems * Powered by **Na/K** gradient * Subject to ***competition***

Question 25

What conjugates are secereted by OAT system?

Answer 25

**Glycine**, **sulph**ates, **glucuronic** acid

Question 26

OCT2 (SLC22A2)

Answer 26

transports ***metformin***

Question 27

OAT1 (SLC22A6)

Answer 27

transports ccidic drug ***Penicillin***

Question 28

Penicillin tubular secretion

Answer 28

**80%** *plasma protein*-**bound** * Expect slow, but is actively *secreted* bt **OAT1** into **proximal** tubule * **HIGH** *elimination* rate *** Probenecid competes *** and *delays* elimination

Question 28

Renal tubular reabsorption

Answer 28

***Passive*** **diffusion** across renal tube * drug ***conc*** reaches **equilibrium** between glomerular and blood > * **[drug]glomerular filtrate** **^** during *reabsorption* of fluid (water) * **^ [drug]gradient** * diffuse back into **blood**

Question 29

Lipid solubility depends on...

Answer 29

**pKa** of molecule and **pH** of the environment (and *LogP* but this cannot be changed) * can influence **excretion** through pH *manipulation*

Question 30

Methamphetamine

Answer 30

***Weak base*** (pKa 9.9) * Secondary Amine may reversibly *accept* proton * Mainly excreted **unchanged** in urine * Un-ionized form reasonably **lipophilic**

Question 31

Methamphetamine Excretion at low pH

Answer 31

Patient administered ammonium chloride to ***acidify*** urine * High *H+* * Base becomes **charged** * Therefore it is **not** *reabsorbed* * ***Urinary excretion ^***

Question 32

Three similar main process control Faecal Excretion

Answer 32

1. ***Passive*** Diffusion 2. **Biliary** Excretion 3. **Enterohepatic** *Recycling*

Question 33

Faecal Elimination 1: Passive Diffusion

Answer 33

*Limited* diffusion from blood to **gut** lumen * Prevent diffusion with ***activated charcoal*** * Stops both **acid** and **base** drugs from *crossing membrane*

Question 34

Faecal Elimination II: Biliary excretion

Answer 34

Liver transports **acids**, **bases** and **non-ionised** molecules to ***bile*** * **>300** Da * *polar* and *lipophillic* * faciliated by **conjugation** (esp. **Glucuronic** acid)

Question 35

Faecal Elimination III: Enterohepatic Recycling

Answer 35

1. Drug conjugate > **bile** 2. **Phase II** conjugate ***hydrolysed*** in **intestine** 3. Active drug ***reabsorbed*** across gut wall 4. Portal vein > **Liver** > **circulation**

Question 36

To what extent does biliary excretion eliminate drugs?

Answer 36

To the extent that enterohepatic recycling is ***incomplete*** (some drug **NOT** *reabsorbed* each time)

Question 37

What is an advantage and disadvantage of using **hair** to detect drug use.

Answer 37

A - can be used when it is ***too late*** to use **blood** or **urine** D - ***differences*** in people (**growth** rates)

Question 38

Hair exists in 3 phases:

Answer 38

1. **Anagen** (*active* growth) 4-8 years, **85%** 2. **Categen** (transition follicle degeneration) 2 weeks, **2-3%** 3. **Telogen** (resting) 10 weeks, **12%** Roughly ***1cm*** per month

Question 38

Can Drugs be Cleaned Out of Hair?

Answer 38

**No!** * Bleaching or harsh treatment may have *some* effect but detection possible * Drug is very ***stable*** in hair

Question 39

Forensic Sampling (Drugs)

Answer 39

* **Blood** > ***CURRENT*** levels * **Urine** > 12h *exposure* * **Hair** > ***background***