Drug Disposition Flashcards
1
Q
How does Coeliac Disease affect drug absorption and first-pass?
A
Reduced intestinal CYP3A expression
2
Q
How does Liver Cirrhosis affect drug absorption and first-pass?
A
Reduced activity of a number of metabolic enzymes
Extent depends on severity of cirrhosis
GFR often impaired
3
Q
How does CKD affect drug absorption and first-pass?
A
Increased gastric emptying time
Increased pH
Altered expression of some CYP450 enzymes
4
Q
How do P-gp and CYP3A4 lower bioavailability?
A
Drug metabolised by CYP3A4 in enterocyte
Remaining drug and metabolite effluxed by P-gp
Drug then into enterocyte and undergoes further metabolism
Cycle reduces amount of drug entering bloodstream unchanged
5
Q
When is absorption perfusion rate limited?
A
Small lipophilic molecules
Very small hydrophilic molecules
Membrane doesn’t provide barrier to drug
6
Q
When is absorption permeability rate limited?
A
Large, polar, hydrophilic molecules
Ionised WA/WB
Membrane is barrier for absorption
7
Q
Give an example of an irreversible inhibition food-drug interaction
A
Furanocoumarins (grapefruit juice) are irreversible inhibitors of intestinal CYP3A4
Prevents metabolism of statin, leading to increased plasma conc.
8
Q
What factors affect the rate of drug distribution?
A
Tissue perfusion Permeability of tissue membranes Physicochemical properties of the drug Binding to plasma proteins (Binding to acidic phospholipids in tissue membranes)
9
Q
How does perfusion affect distribution equilibrium?
A
Equilibrium achieved fasted in more highly perfused tissues
10
Q
What tissues are considered highly perfused?
A
Lungs
Kidneys
Liver
Brain
11
Q
What tissues are considered poorly perfused?
A
Muscle
Skin
Adipose
12
Q
At what level is the distribution barrier in muscles and the brain and why?
A
Brain - Capillary level, very small pores
Muscle - Cellular level, more porous capillaries
13
Q
What affects drug distribution at equilibrium?
A
Binding to plasma proteins and tissue components
14
Q
What is the volume of plasma in the body?
A
3L
15
Q
What is the volume outside the plasma in the body? What does this include?
A
39L
Extracellular space + cellular space
16
Q
Define the amount of the body as an equation
A
V.C
Vp.C + Vtw.Ct (amount in plasma + amount outside plasma
17
Q
Define the fraction unbound in plasma and tissues (equation)
A
fu = Cu/C fu(t) = Cu(t)/C(t)
18
Q
What determines the volume of distribution?
A
Relative balance of drug binding in plasma compared to tissues
19
Q
What parameters result in high volume of distribution?
A
High fu or low fu(t)
20
Q
What are the roles of hepatic uptake and efflux transporters?
A
Uptake - Active uptake of drugs into hepatocytes
Efflux - Excretion of drug into bile
21
Q
What is the relevance of Cu=Cu(t)?
A
Distribution equilibrium reached, no active processes (passive diffusion)
22
Q
Why may Cu be more than Cu(t)?
A
Metabolism in tissues
Efflux transporters
23
Q
Why may Cu be less than Cu(t)?
A
Uptake transporters
24
Q
What can cause different V values from measuring different reference fluids?
A
Drug binding to proteins or cell components
25
Why is V clinically relevant?
To find an appropriate loading dose for a drug
26
Define the fraction of drug in the body in plasma and outside plasma
In plasma, V(p)/V
| Outside of plasma, 1-V(p)/V
27
Why is unbound concentration important?
Only unbound drug can diffuse into tissues for pharmacological effect or to be eliminated
28
What is the most common cause of DDIs?
Inhibition of metabolic enzymes in liver and intestine
29
Why is metabolism important?
Dominant elimination route
| Prevents drug accumulation
30
Give two examples of pharmacologically active metabolites
Ezetimibe Glucuronide
| Morphine-6-Glucuronide
31
Give to examples of inhibiting metabolites
Gemfibrozil glucuronide
| Itraconazole metabolites
32
What is the role of the liver in drug metabolism/elimination?
Most important metabolising organ due to size, blood flow and high enzyme concentrations
First-pass metabolism
33
What are classed as phase 1 reactions?
Oxidation
Reduction
Hydrolysis
34
What is classes as a phase 2 reaction?
Conjugation
35
Which family of enzymes catalyses oxidation reactions?
Cytochrome P450s
36
What is the purpose of phase 1 reactions?
Introduce or expose functional groups
37
What happens in oxidation of C atoms?
Hydroxylation of aromatic or aliphatic carbons
38
What happens in oxidation to N or S atoms?
Cleavage of alkyl group
| Oxidation of N and S
39
What functional groups are susceptible to reduction?
Nitro and keto groups
40
What functional groups are susceptible to hydrolysis?
Ester and amide groups
41
Where can sequential oxidation occur?
On the same C or on a different C
42
Describe the properties of metabolites and how they are excreted
More polar and hydrophilic than the parent drug, really excreted
43
What are the routes of excretion?
Renal
Hepatic (biliary)
Pulmonary
44
What is clearance?
Relates rate of drug elimination to concentration (units L/hr)
Volume of plasma cleared of drug per unit of time
45
When is clearance independent of dose?
When drug pharmacokinetics are linear
46
What is the elimination half life?
The time taken for the plasma concentration to fall by half once the distribution equilibrium has been achieved
47
Why do clearance values vary between drugs?
Degree of extraction through elimination organ
48
What are the typical blood flow values?
Liver: 1300-1500ml/min
Kidney: 1100ml/min
Cardiac Output: 6000ml/min
49
What are the values for low, medium and high hepatic extraction ratio?
Low: <0.3
Medium: 0.3-0.7
High: >0.7
50
What is additivity of clearance?
Rate of elimination is equal to the combined rates of excretion and hepatic metabolism
51
What is hepatic clearance determined by?
Hepatic blood flow and hepatic extraction ratio
52
What factors can influence hepatic clearance?
```
Hepatic blood flow
Plasma protein binding
Enzyme activity
Disease status
Transporter activity
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53
When does blood flow have a significant effect on hepatic clearance?
Drugs with an extraction ratio >70%
54
What are the structural requirements for biliary excretion?
Polar molecules
| MW >350
55
Describe the process of enterohepatic circulation
Small intestine to superior mesenteric vein to portal vein to liver
Excreted in bile duct and re enters small intestine
56
How does enterohepatic circulation impact plasma-concentration profile?
Plasma concentration increases after dropping as drug is reabsorbed from bile in small intestine (peaks and troughs)
57
What are the components of a CYP system?
Haemoproteins - Cytochrome P450, Cytochrome b5
Flavoproteins - FP1 (NADPH-cytochrome P450 reductase), FP2 (NADH-cytochrome b5 reductase)
Phospholipid membrane
58
What are the two binding sites on CYPs?
Substrate binds to active site
| O2 binds to haem ligand
59
Give an example of a substrate metabolised by CYP2D6
Ecstasy
60
Give an example of a substrate metabolised by CYP2C9
Tolbutamide
61
Give two examples of substrates metabolised by CYP3A4
Midazolam
| Testosterone
62
What is a common cause of DDIs?
2 or more drugs metabolised by the same CYP
63
Describe the three types of CYP2D6 metabolisers and how drug regimens should be altered
Poor Metaboliser - Lacks gene, higher plasma conc, increased side effects. Reduce dose
Extensive Metaboliser - Normal activity. Normal dosing
Ultra-Rapid Metaboliser - Gene duplication, lower plasma concentrations, therapeutic failure. Consider increasing dose
64
Give an example of a drug that is metabolised by CYP2D6 to produce a pharmacologically active metabolite
Codeine
65
What are the types of metabolic DDIs?
Induction - Increased synthesis or activity of metabolic enzymes
Reversible Inhibition - Enzyme-Inhibitor complex formed but enzyme activity recovered after removal of inhibitor
Irreversible Inhibition - Covalent binding to enzyme inactivates it, activity restored when new enzymes synthesised
66
What are the classifications of drugs as CYP inhibitors?
Weak: 1.25-2-fold increase in AUC
Moderate: 2-5-fold increase in AUC
Strong: >5-fold increase in AUC
67
Give an example of a reversible inhibition DDI
Ketoconazole inhibits CYP3A4
Terfenadine metabolism to fexofenadine inhibited
Terfenadine cardiotoxic at higher concentrations (QT prolongation, severe cardiac arrhythmia)
68
How does Ritonavir act as a booster for HIV protease inhibitors?
Ritonavir is an irreversible inhibitor of CYP3A4, increasing plasma concentrations and effect of HIV protease inhibitors
HIV protease inhibitors can be given at a lower dose to avoid side effects
69
Give an example of a drug that increase its own metabolism
What is this known as?
Carbamazepine
Autoinduction
70
Which CYP enzymes are induced by Phenobarbital, Rifampicin, Phenytoin, Carbamazepine?
CYP3A4, 3A5, 2C9, 2B6
71
What CYP enzyme is induced by cigarette smoke?
CYP1A2
72
Which non-CYP enzymes are induced by Rifampicin and Phenobarbital?
UGT1A
73
Which non-CYP enzyme is induced by carbamazepine?
UGT2B7
74
Describe the mechanism of induction
Increased transcription of DNA to mRNA
Increased Translation of mRNA to enzymes
Decreased degradation of enzymes
75
What are the roles of OATP1B1 and OAT1B3?
1B1 - Mediates uptake of therapeutic drugs in hepatocytes and endogenous compounds
1B3 - Substrate overlap, uptake of glutathione
76
What is the clinical effect of inhibiting OATP transporters?
Increased plasma concentrations and risk of adverse effects
77
Give some examples of OATP1B1 inhibition DDIs
Cyclosporin inhibits, increases plasma conc. of statins
Single dose of Rifampicin inhibits uptake of Glibenclamide
Lopinavir and Ritonavir inhibits uptake of Rosuvastatin
78
Which P-gp DDIs are most relevant and why?
Digoxin as a substrate
| Narrow therapeutic index
79
Give some examples of transporter food-drug interactions
Turmeric inhibits BCRP, efflux of sulfasalazine is inhibited so increased effect/side effects
Apple juice inhibits OAT2B1, reduced plasma conc. of aliskiren and fexofenadine
80
Give an example where changes in systemic exposure may not reflect an effect on tissue distribution
Metformin DDIs (OCT/MATE)
81
What is the purpose of endogenous biomarkers?
Many are transporter substrates
| Monitoring change in biomarker AUC to predict drug AUC change
82
What is the purpose of PET imaging in DDIs? What are the ideal properties?
Investigate changes in tissue pharmacokinetics
| Transporter specific, metabolically stable, amenable to radiolabelling
83
Give two examples of inhibiting metabolites and what they inhibit
N-desmethyl diltiazem - Metabolic enzymes
| Cyclosporine AM1 - Uptake transporters
84
What are the mechanisms of renal drug excretion?
Filtration
Reabsorption
Active Secretion
85
What is the average flow and pH of urine?
1-2ml/min
| pH 4.5-7.6
86
Define the rate of renal excretion (equation)
CLr.C plasma
| rate of filtration + rate of secretion)x(1 - fraction reabsorbed
87
What is glomerular filtration and how is renal clearance by filtration worked out?
Passive process filtering unbound drug in plasma water
| CLr = fu.GFR
88
What are the average GFR values for men and women?
120ml/min - Men
| 110ml/min - Women
89
How is GFR determined?
Inulin or creatinine as fu=1 and they are not secreted or reabsorbed
90
What is the purpose of active secretion?
Adds drug to tubular to facilitate excretion
| Saturable process
91
What is the mechanism of active secretion?
Active uptake via transporters, efflux transporters move drugs into tubule
92
What is the DDI between Penicillin G and Probenecid?
Probenecid inhibits organic anion transporters in kidney tubule preventing active secretion of penicillin, results in higher plasma concentrations of penicillin
93
When does reabsorption from the kidney tubule occur?
Unbound and non-ionised drug can be reabsorbed (needs to be lipophilic enough)
94
When are weak acids susceptible to reabsorption?
pKa 3-7.5 as they will be mostly unionised over urine pH range
95
When are weak bases susceptible to reabsorption?
pKa 6-12 as they will be mostly unionised over urine pH range
96
When is renal clearance dependent on urine flow?
When reabsorption equilibrium has been reached - higher volume of urine increases renal clearance
97
What is the purpose of forced diuresis?
Altered urine pH in drug overdose can be used to increase elimination
Only effective if renal excretion is significant
98
How are the mechanisms of renal elimination identified?
CLr = fu.GFR, filtration
CLr > fu.GFR, secretion
CLr < fu.GFR, reabsorption
99
What metabolising enzymes are present in the kidney tubule?
CYP3A5, 2D6, UGT1A9, 2B7, carboxylesterases
100
When should dose adjustments be made in renal impairment?
fe is >50%
Narrow therapeutic window
Produces active metabolites
Metabolism is impaired
101
Describe the properties of conjugates
Extremely polar
pKa <3
Terminal metabolites
102
How are conjugates excreted?
Biliary excretion
Renal excretion
Via efflux transporters (MRP2/4)
103
What are the phase 2 reactions for OH, COOH and NH2 functional groups?
OH - Glucuronidation or Sulphation
COOH - Glucuronidation or Glycine conjugation
NH2 - Glucuronidation or Acetylation
104
Give two examples of direct conjugation and the enzymes involved
Midazolam -> Midazolam N-glucuronide (UGT1A4)
| Naloxone -> Naloxone Glucuronide (UGT2B7)
105
What are the enzymes and cofactors required for glucuronidation?
Enzyme - UDP-glucuronosyltransferases (UGT)
| Cofactor - UDP glucuronic acid (UDPGA)
106
Give an example of a toxic glucuronide
Acyl glucuronide of NSAIDs cause renal toxicity
107
Give an example of a glucuronide DDI
Gemfibrozil glucuronide inhibits OATP1B1 and CYP2C8 - prevents metabolism of Cerivastatin
108
What is Gilbert's Syndrome?
Deficiency of UGT1A1, results in unconjugated hyperbilirubinaemia
109
What are the enzymes and cofactors required for sulphation?
SULT1A1 enzyme
| Cofactor - PAPS
110
What is required for glycine conjugation?
Drug activated as acyl coenzyme A intermediate
| Glutathione conjugation
111
What is required for acetylation?
Coenzyme - Acetyl CoA
Amines - N-acetyl conjugates formed
N-acetyl transferase enzyme
112
What are phase 3 reactions and what are their purpose?
Hydrolysis of biliary metabolites by glucuronidase or sulphatase in small intestine
Prolongs drug effect
113
What are the types of non-inert metabolites?
Pharmacologically active metabolites (mainly phase 1 metabolites)
Reactive metabolites (N-OH metabolite in paracetamol overdose, ADRs)
Metabolites contributing to DDIs (inhibition of metabolic enzymes and transporters)
114
What affects action of pharmacologically active metabolites?
Balance of formation rate and elimination rate (plasma concentration)
Receptor affinity
115
Give an example of pharmacologically active metabolites
Diazepam Metabolites:
Nordiazepam is pharmacologically active
Temazepam and Oxazepam are rapidly metabolised although pharmacologically active, marketed as short-acting alternatives
116
Give two examples of chemically-reactive metabolites
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Benzopyrene (polycyclic aromatic hydrocarbon in cigarette smoke) forms reactive metabolites in lung
Paracetamol metabolites (NAPQI) cause liver failure in cases of overdose
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117
How are reactive metabolites protected?
Conjugation to glutathione
| N-acetyl cysteine
118
What are type A ADRs?
Reversible, usually dose related
A1 - Effect linked to pharmacological action
A2 - Effect unrelated to drug action
119
What are type B ADRs?
Often have a genetic basis, immune mediated toxicity
Metabolite binds to protein and is recognised as an antigen, creating an immune response
Commonly associated with liver
120
What are type C ADRs?
Often lead to cell death and tissue necrosis - necrotic toxicity
Chemical reaction between drug/metabolite with tissue macromolecules
Commonly associated with liver
121
What are type D ADRs?
Similar to type B and C but delayed response - chronic toxicity
Teratogenic
Mutagenic
Carcinogenic
122
Give an example of a weakly acidic drug where the elimination is urine pH dependent
Sulphamethoxazole
