PK 07: Clearance – Physiological Concepts Flashcards
Where does drug metabolism occur?
- primarily in the liver
- also in small intestine, kidney, lung
What is phase I of drug metabolism?
oxidation, reduction, hydrolysis
- introduces or unmasks polar functional groups such as –OH (hydroxyl), NH2 (amino), or –SH (sulfhydryl) that may be subject to phase 2 metabolism
- facilitated by the presence of drug metabolizing enzymes called cytochrome P450 enzymes (CYPs)
What is phase II of drug metabolism?
glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids
- addition of an endogenous hydrophilic group to form a larger, polar, water-soluble, inactive metabolite that is easier to excrete
- normally follows phase I metabolism, but can occur independently
- facilitated by mainly UDP-glucuronosyltransferases (UGT1 and UGT2), but also sulfotransferases (SULTs), N-acetyltransferases (NATs), glutathione S-transferases (GULTs), methyltransferases
What is the major route for drug excretion?
urine (kidney)
- polar, water-soluble non-volatile, and unbound compounds undergo renal excretion
- mechanisms of renal drug clearance: glomerular filtration (passive), tubular secretion (active), tubular reabsorption (active/passive)
What are the minor routes for drug excretion?
- bile (liver)
- exhalation
- sweat
- lactation
Describe the bile (liver) route for drug excretion.
- active transport
- excreted drugs are polar (hydrophilic) and MW > 350 g/mol
- excreted drugs entering GI tract can be excreted via feces or reabsorbed via enterohepatic circulation
Estimating Total Body Clearance
assume blood clearance is equivalent to plasma clearance
What is fe?
fraction of drug excreted unchanged in the urine
What is 1-fe?
fraction of drug eliminated by other processes – usually assumed to be the fraction of drug metabolized (fm)
What is the shortcut for evaluating fe and renal vs. hepatic clearance?
- fe > 0.5: renal clearance more important
- fe < 0.5: hepatic clearance more important
- fe = 0.5: hepatic and renal clearance equally as important
What is the organ-specific extraction ratio (E)?
fraction of drug presented to the organ that is eliminated during one pass
- drugs are categorized based on efficiency of the organ at eliminating the drug
What is the E for a high E drug?
> 0.7
What is the E for a low E drug?
< 0.3
What is the E for a moderate E drug?
0.3-0.7
What is linear PK?
rates of drug absorption, distribution, and elimination are governed by first-order processes – rates are directly proportional to the amount/concentration of drug present
- dose-independent
- time-independent
Describe how PK parameters change with linear PK.
PK parameters (CL, V, t1/2) remain constant
What is non-linear PK?
rates of drug absorption, distribution, and elimination are governed by non-linear processes – rates are not directly proportional to the amount/concentration of drug present
- dose-dependent
- time-dependent
Describe how PK parameters change with non-linear PK.
PK parameters change with dose or time
What are the causes of non-linear PK?
saturation of one or more of the key PK processes
- saturable metabolism (most common – see below)
- saturable excretory transport
- saturable plasma protein or tissue-binding
- saturable absorption
- saturable first-pass
time-dependent changes in PK parameters
- auto-induction
- auto-inhibition
When does saturation of metabolic clearance occur?
occurs at high drug concentrations when capacity of eliminating enzyme system is overwhelmed (ie. saturation)
- enzyme system is functioning at or near its maximum capacity (capacity-limited metabolism)
What is the Michalis-Menten model?
describes enzyme-specific drug metabolism in-vitro
- can also be applied to describe in-vivo drug metabolism
What is the effect of metabolic saturation on half-life (t1/2)?
increases t1/2
