Lecture 3 Disposition of Toxicants Flashcards
What are xenobiotics?
A chemical compound foreign to a given biological system. Environmental chemicals including both man-made and natural sources.
What are the determinants of absorption? (2)
Concentration Partition coefficient (ratio of unionised drug in organic vs. aqueous phase)
What is Fick’s law of diffusion? Thus what conditions is diffusion favoured?
Diffusion is dependent on concentration gradient, thickness and permeability of the barrier between two compartments, permeability coefficient of xenobiotic in the medium, surface area.
To what extent are strong acids/bases ionised?
Fully ionised at every pH
To what extent are weak acids/bases ionised? How can we calculate the extent of ionisation?
The extent of ionisation depends on the pH of the environment. This can be calculated by the Henderson-Hasselbalch equation pH = pKa + log [A-]/[HA]
In which form of absorption does pre-systemic circulation occur?
Oral administration because undergoes gut absorption and metabolism before enters circulation
Define bioavailability.
The proportion of administered xenobiotic/drug which reaches the systemic circulation
Is distribution more passive or active?
Can be passive and active, but most definitely more active even for highly lipid soluble drugs.
What factors determines distribution?
Water/lipid solubility, transporter substrates of drug, blood flow, body composition (more lipid or muscle), transporter expression, protein binding, integrity of barrier
Which metabolism method is the most predominant?
85% of metabolism occurs by conjugation
Where does Phase I and Phase II metabolism occur?
Liver, also in lung, kidney, intestine but of low significance
If a drug has been metabolised by either Phase I and Phase II metabolism, what are the possible forms of excretion and via which organ?
Urine from kidney
Bile from gallbladder, into faeces
What is the general purpose of metabolism?
To increase hydrophilicity so allow ease of excretion
Describe induction of CYPS and the consequences of induction. Give an example.
Induction occurs when exposure to some drugs or chemicals increases the activity of CYPs in tissues. This increased enzymatic activity means more drug is cleared thus greater doses needed to achieve same therapeutic response, or toxicity is experienced when exposure to inductive drug/chemical ceases.
CYP1A2 induction by cigarette smoke, dioxins.
How do drug metabolites leave the cell?
Drug metabolites are highly polar so cannot move through plasma membrane and must use efflux transporters in particular ATP-binding cassette transporters.
What are the three forms of movement in renal elimination?
Glomerular filtration: movement of metabolite from glomerulus to Bowman’s capsule, only occurs for free unbound drug metabolite
Active tubular secretion: ATP-dependent movement from renal tubule into urinary excretion.
Tubular reabsorption: passive process where drug diffuses from urine back into blood due to concentration gradient
What are two reasons why chemicals appear in faeces?
1) drug was never absorbed or metabolised, went straight through GIT to be excreted in faeces
2) drug was absorbed and metabolised by liver, then excreted in bile which exits via intestines into faeces
What is enterohepatic recycling?
After metabolites are deposited in intestines from the bile, it may be cleave by gut bacteria, where a portion of the metabolite may be reabsorbed by intestines. Available for secondary phase of therapeutic effect
What sort of drugs are excreted by the lungs? (2)
Drugs that are gases and volatile substances that do not require metabolism
Drugs that are metabolised in part to CO2
