absorption, distribution, and excretion (trush)
TRANSCRIPT
![Page 1: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/1.jpg)
Copyright 2008, The Johns Hopkins University and Michael A. Trush. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site.
![Page 2: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/2.jpg)
Absorption, Distribution, and Excretion
Michael A. Trush, PhD Bloomberg School of Public Health
![Page 3: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/3.jpg)
Section A
The Toxicological Process
![Page 4: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/4.jpg)
4
Definition
Toxicology is the study of poisonsPoisons are chemical/physical agents that produce adverse responses in biological organisms
![Page 5: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/5.jpg)
5
“What is there thatis not poison? Allthings are poisonand nothing withoutpoison. Solely, thedose determines that a thing is nota poison”
Paracelsus (1493-1541)
![Page 6: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/6.jpg)
6
The Toxicological Paradigm
![Page 7: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/7.jpg)
7
ToxicokineticsToxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants. In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time pointsThe end result of these toxicokinetic processes is a biologically effective dose of the toxicant.
![Page 8: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/8.jpg)
8
Toxicodynamics
Toxicodynamics refers to the molecular, biochemical, and physiological effects of toxicants or their metabolites in biological systemsThese effects are result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target
![Page 9: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/9.jpg)
9
Molecular Targets Concept
The toxic action of a chemical is a consequence of the physical/chemical interaction of the active form of that chemical with a molecular target within the living organism
Continued
![Page 10: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/10.jpg)
10
Molecular Targets Concept
![Page 11: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/11.jpg)
11
Examples of Molecular Targets
Proteins–
Arylhydrocarbon(Ah) receptor—Dioxin
–
Hemoglobin—COLipids—Carbon tetrachlorideDNA—Aflatoxin
![Page 12: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/12.jpg)
12
Dose-Response Concept
The magnitude of the toxic effect will be a function of the concentration of altered molecular targets, which in turn is related to the concentration of the active form of the toxicant( biologically effective dose) at the site where the molecular targets are located.
![Page 13: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/13.jpg)
13
The Toxicological Process
![Page 14: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/14.jpg)
14
The Toxicological Process
![Page 15: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/15.jpg)
Section B
Transport Process Mechanisms
![Page 16: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/16.jpg)
16
Membrane Transport of Xenobiotics
The absorption, distribution, and excretion of xenobioticsinvolves passing through various cell and organ membranes. This occurs through various transport mechanisms
![Page 17: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/17.jpg)
17
Membrane Transport of Xenobiotics
![Page 18: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/18.jpg)
18
Xenobiotics: Transport Mechanisms
Factors affecting membrane transport of chemicals:–
Molecular weight/shape
–
Charge–
Lipid solubility
–
Membrane composition–
Membrane thickness
![Page 19: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/19.jpg)
19
Types of Transport
Simple diffusionFacilitated diffusionActive transportPinocytosis/receptor-mediated uptakeFiltration
![Page 20: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/20.jpg)
20
Types of Transport
![Page 21: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/21.jpg)
21
Characteristics of Simple Diffusion
Transport proceeds in the direction of the electrochemical potential (concentration) gradientTransport is not saturable at high concentration gradientsNo structural specificityNo energy requirementInherently symmetrical transport
![Page 22: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/22.jpg)
22
BOTH PASSIVE MEDIATED and ACTIVE MEDIATED TRANSPORT
INVOLVE the USE of CARRIER PROTEINS
![Page 23: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/23.jpg)
23
Carrier-Mediated Transport
![Page 24: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/24.jpg)
24
Characteristics of Passive Mediated Transport
Transport proceeds in the direction of the electrochemical potential (concentration) gradientThe process is saturable at high concentration gradients, i.e., there is a maximum rate of transport
Continued
![Page 25: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/25.jpg)
25
Characteristics of Passive Mediated Transport
Structural specificity (specific inhibitors)No energy requirementsInherently symmetrical transport
![Page 26: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/26.jpg)
26
Characteristics of Active Mediated Transport
Transport can proceed against an electrochemical potential (concentration) gradientThe process is saturable at high concentration gradientsStructural specificityRequires cellular energyAsymmetrical transport
![Page 27: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/27.jpg)
27
Active Mediated Transport
The structure of the herbicide paraquat (A) and the polyamines putrescine (B) and spermine (C)
![Page 28: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/28.jpg)
28
Pinocytosis/Phagocytosis/ Receptor Mediated Endocytosis
cell membrane
PINOCYTOSIS
Pinocytic vessels
PHAGOCYTOSIS
pseudopodsP
inoc
ytos
isch
anne
l
![Page 29: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/29.jpg)
29
Filtration
Transport of solutes as a consequence of bulk flow of fluid (aqueous) phaseGlomerulus of kidney is a good example of site where filtration occurs
![Page 30: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/30.jpg)
Section C
Toxicokinetics
![Page 31: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/31.jpg)
31
Systemic Kinetics: Outline
Physiological basis of toxicokineticsBiliary excretion route for foreign compoundsBarriersMajor difference between a general (non-neural) and brain capillaryExcretion pathways
![Page 32: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/32.jpg)
32
![Page 33: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/33.jpg)
33
Biliary Excretion Route For Foreign Compounds
Image source: NIH/NIDDK. Public Domain.
![Page 34: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/34.jpg)
34
Systemic Kinetics: Barriers
Blood-brain barrierPlacentaBlood-testicular barrier
![Page 35: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/35.jpg)
35
Major Difference between a General (Non-Neural) and a Brain Capillary
![Page 36: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/36.jpg)
36
Excretion Pathways
Respiratory excretion–
Mucocilliary clearance
Gastrointestinal excretion–
Biliary excretion
–
Entero-hepatic circulationUrinary excretion–
Glomerular filtration
–
Trans-tubular secretion
![Page 37: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/37.jpg)
37
Afferent arteriole
Efferent arterioleGlomerulus
Bowman’s capsule
Proximal tubule Water soluble
Lipid soluble
Filtered drugPassive
reabsorption
Excretion and/or further passive reabsorption
Unfiltered drug
Activesecretion
Renal Excretion of Chemicals
![Page 38: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/38.jpg)
38
Other Routes of Excretion
MilkSweatHairNailsSaliva
![Page 39: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/39.jpg)
39
Biological Half Life
The biological half-life (T1/2) is the time required for some measure of the amount of a chemical in the body (for example, body burden, tissue concentration) to decrease to 1/2 its value at the beginning of the observational interval
Continued
![Page 40: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/40.jpg)
Section D
Toxicokinetics and PBK Modeling
![Page 41: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/41.jpg)
41
PBPK Modeling Physiologically Based Pharmacokinetic (Toxicokinetic)
Purpose–
To mathematically model how a substance is absorbed, distributed, and metabolized in the body to reduce uncertainties in determining the estimated dose
![Page 42: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/42.jpg)
42
PBPK Modeling
Source: Casarett & Doull, Chaps. 5 and 7, 1996 Continued
![Page 43: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/43.jpg)
Tox, lec 1, slide 6
![Page 44: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/44.jpg)
44
PBPK Modeling Blood Styrene Levels: Rat vs. Human
![Page 45: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/45.jpg)
45
Vinyl Chloride Metabolism
Covalent binding to proteins
H
CC
H
ClH
O
Chloroacetaldehyde
GSH conjugation
P450
![Page 46: Absorption, Distribution, and Excretion (Trush)](https://reader031.vdocuments.site/reader031/viewer/2022021419/58776df01a28abd0398b83ff/html5/thumbnails/46.jpg)
46
Vinyl Chloride – Exposure, Metabolism in Rats & the Incidence of Hepatic Angiosarcoma
Exposure μg of VC per L of air μg of VC metabolized/4 hr Incidence %
50 128 739 2
250 640 2435 7
500 1,280 3413 12
2,500 6,400 5030 22
6,000 15,360 5003 22
10,000 25,600 5521 15
Data source: Gehring
et al. Toxicol Appl Pharmacol. 1978;44:581-591