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Pharmacology > Drug Disposition PED2001 > Flashcards

Drug Disposition PED2001 Flashcards

1
Q

What are the 2 types of drug movement around the body

A

Bulk flow transfer in the blood; chemical nature if drug has no effect

Diffusional transfer; differs between drugs with different chemical properties

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2
Q

What are the main factors affecting GI absorption

A

GI motility
Splanchnic blood flow
Particle size and formulation
Physicochemical factors

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3
Q

Describe drug absorption from the intestines

A

By passive transfer
Rate determined by the ionisation and lipid solubility of drug molecules

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4
Q

How does a migraine affect gastrointestinal motility

A

Causes gastric stasis and decreases drug absorption

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5
Q

Describe systemic availability

A

The amount of drug that reaches the systemic circulation intact and the rate at which it happens

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6
Q

What is a problem that occurs when using topically applied drugs

A

Variability in drug administration through skin = lack of precision regarding the real dose absorbed

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7
Q

Why are new topical dosage forms important

A

Design emphasis on systemic input

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8
Q

What is the energy source for a transdermal drugs

A

The difference in the drugs chemical potential between the reservoir and the systems exterior

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9
Q

What ensures a consistent rather of delivery with transdermal drugs

A

Presence of excess drug in reservoir

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10
Q

Why would a transdermal drug delivery be used

A

Patient compliance issues
Gastric irritation w oral therapy
Side effects with respective conventional dosage

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11
Q

What are the factors that need to me considered when formulating oral drugs

A

Rate of disintegration on the tablet
The rate of dissolution on the drug particles in the intestinal fluid

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12
Q

What physical factored affect pharmaceutical availability of oral drugs

A

Tablet compression and excipients
Other tablet excipients
The form of the drug
Particle size

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13
Q

What does bioinequivalent mean

A

When 2 formulations of a drug with a significant difference in bioavailability

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14
Q

What does therapeutic equivalence mean

A

When similar drugs have comparable efficacy and safety

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15
Q

What determines the route of administration

A

Therapeutic objective
Properties of the drug

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16
Q

How can the effect of injected local anaesthetic be prolonged

A

The formation contains adrenaline
Causes vasoconstriction = preventing the drug to be carried away by circulation

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17
Q

What forms of drug will avoid 1st pass metabolism

A

Sunlingual, buccal, rectal and transdermal formulations

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18
Q

How can you reduce the risk of gastric erosions

A

Delayed-release and slow release formulations
= less frequent administrations compared to conventional formulations

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19
Q

What is the minimum criteria to be met for combination products in oral therapy

A
  1. The frequency of administration of the 2 drugs is the same
  2. Fixed doses in the product are therapeutically and optimally effective
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20
Q

What is the potentials vantage of combination formulations

A

Improved compliance
Ease of administration
Synergistic or additive effects
Decreased adverse effects

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21
Q

Give 3 examples of special drug delivery systems

A

Biologically erodable microspheres loaded w drugs
Pro-drugs
Antibody-drug conjugates

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22
Q

Describe drug distribution

A

Process by which a drug reversible leaves the blood stream and enters the interstitium

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23
Q

What factors does drug distribution rely on

A

Blood flow
Capillary permeability
The degree of drug binding to plasma and proteins
The relative hydrophobicity of the drug

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24
Q

Why does blood flow to tissue capillaries vary

A

Consequence of unequal cardiac output to various organs

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25
Q

What determines capillary permeability

A

Capillary structure
Drying structure

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26
Q

What allows drugs to exchange freely between blood and liver interstitium

A

Large fenestrations

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27
Q

How do drugs pass the blood-brain barrier

A

Drugs must pass through the endothelial cells of the capillaries of CNS
Or actively transported

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28
Q

What drugs can and can’t penetrate the CNS

A

Can: lipid soluble
Can’t: ionised or polar drugs

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29
Q

How do hydrophilic and hydrophobic drugs cross membrane

A

Hydrophobic: readily across the membrane
Hydrophilic: through slit junctions

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30
Q

What is a major factor in the distribution of hydrophobic drugs

A

Blood flow to the area

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31
Q

What does it mean if a drug is trapped in the plasma compartment

A

Drug has a large MW or binds extensively to plasma proteins
Too large to move out through slit junctions of capillaries

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32
Q

What does it mean if the drug is trapped n the extracellular fluid

A

Drug has a low MW but if hydrophobic
Can move into interstitial fluid but unable to cross lipid membrane and enter intracellular fluid

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33
Q

What is the Vd if the drug is in the plasma compartment

A

Vd = plasma water

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34
Q

What is the Vd of a drug in the extracellular fluid

A

Vd = plasma water + extracellular fluid volume

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35
Q

What does it mean if the drug is trapped in total body water

A

The drug has a low MW and is hydrophobic
It can move through slit junctions and cross cell membranes into intracellular fluid

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36
Q

What is the Vd for a drug in total body water

A

Vd = plasma water + extracellular + intracellular volumes

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37
Q

What does it mean if a drug is bound

A

They’re pharmacologically inactive and are unable to reach target site to elicit a biological response

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38
Q

Describe the binding capacity of albumin

A

Has high capacity and low capacity

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39
Q

What types of drugs does albumin have the strongest affinity for

A

Anionic and hydrophobic drugs

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40
Q

What are the 2 classes of drugs w high affinity for albumin

A

Class I and Class II

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41
Q

What does it mean to be a class I drug

A

Dose of drug < binding capacity of albumin
Binding sites in excess of the available drug = fraction of frug bound is high

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42
Q

What does it mean to be a class II drugs

A

Dose of drug > number of albumin binding sites
= relatively high proportion of drug exists in free state

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43
Q

What is the clinical importance of drug displacement

A

The administration of class II drugs too displace class i drugs to increase their free state

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44
Q

What happens if the Vd is large

A

Then change in free drug conc is insignificant

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45
Q

What happens if the Vd is small

A

The newly displaces drug does not move into the tissue as much
= Increase in plasma drug conc more profound

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46
Q

What is enterohepatic circulation

A

When endogenous compounds are conjugated and excreted into the GI tract
Then they’re deconjugated and reabsorbed into systemic circulation

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47
Q

What is Phase I metabolism

A

A functional group is introduced normally producing a more polar and excretable molecule

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48
Q

What CYP450 is responsible for metabolising 50% of drugs

A

CYP3A4 - found most abundantly in liver and gut

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49
Q

What is phase II metabolism

A

Conjugate reactions which detoxify compounds and prepare them for excretion

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50
Q

When does a compound skip phase I metabolism and got straight to phase II

A

When there are subtle functional groups for conjugation already present on the molecule

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51
Q

Give 3 examples of phase II enzymes

A

UDP-glucuronosyltransferases UGTs
Sulfotransferases SULTs
Glutathione-S-transferases GSTs
N-acetyltransferases NATs
Methyltransferases

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52
Q

How can the loss in first pass metabolism be compensated for using oral drugs

A

Give a much higher dose

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53
Q

How does first pass metabolism affect an oral drugs bioavailability

A

Reduces it

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54
Q

What factors can affect first pass metabolism

A

Genetics variations between individuals in liver and GI
Variations between GI and liver blood flow
Gut microbiota

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55
Q

What is a prodrug

A

A drug that is administered as an inactive form and requires metabolism to become active

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56
Q

What are the benefits of pro drugs

A

Improves PK and decreases toxicity

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57
Q

Give an example of a prodrug

A

Codeine -> morphine
Metabolised by CYP2D6 demethylation

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58
Q

What are the main families of CYP450s that metabolise xenobiotics

A

1,2 and 3

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59
Q

Describe the prosthetic group of CYP450s

A

Haem containing Fe (III)
6th position os water in the absence of substrate binding

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60
Q

What is the cytochrome P450 reaction

A

DH + NADPH +O2 —> DOH + NADP + H2O

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61
Q

What are the 3 necessary components of a P450 reaction

A

CYP450 enzyme
NADPH-CYP450 reductase
Phosphatidylcholine

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62
Q

What is the purpose of NADPH in the CYP450 reaction

A

Supplies 2 protons and 2 electrons in electron transfer process

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63
Q

Describe the function of NADPH-CYP450 reductase

A

Accessory enzyme that interacts w CYP450 enzyme and transfer e- from NAPDH

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64
Q

What prosthetic group do NADPH-CYP450 reductases contain

A

Flavin adenine dinucleotide (FAD)
Flavin mononucleotide (FMN)

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65
Q

Describe the structure of CYP450s and the reductase on the enzyme

A

CYP450s membrane bound and the reductase fits between 2 monomers and is shared

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66
Q

What does an induction of CYP450s represent

A

Increase in the amount of mRNA and protein

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67
Q

What is the effect of CYP450 mediated reactions

A

Inactivate many drugs and increase their rate of reaction

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68
Q

How a CYP450 isoforms produced

A

Produced from different genes

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69
Q

Why are P450s important in drug metabolism

A

70-80% of all drugs subject to metabolism are P450 substrates
Almost 90% are metabolised by CYP3A4/2D6 and 2C9

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70
Q

What are the 3 ways to identify specific P450 isoforms responsible for metabolism of a drug

A

Correlation analysis using human liver microsome bank
Inhibition studies
Studies using purified or expressed enzymes

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71
Q

Describe CYP2D6

A

Substrates typically have a basic nitrogen and a hydrophobic region
Most substrates are either cardiovascular agents, antipsychotics or antidepressant
Common reaction: Hydroxylation

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72
Q

Name a substrate of CYP2D6

A

Antiarrhythmics
B-blockers
Antihypertensives
Neuroleptics
MAO inhibitors
Analgesics

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73
Q

Describe CYP2C9

A

Substrates tend to have areas of strong H-bonds
Target manny different fruity ones but especially NSAIDs
Subject to genetic SNPs
Induced by barbiturates and rifampicin

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74
Q

Name a substrate of CYP2C9

A

Ibuprofen
Naproxen
Warfarin
THC

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75
Q

Describe CYP3A4

A

Highly induced by glucocorticoids and rifampicin
Has considerable structural diversity in substrate
Binding site can accommodate large molecules -> hydrophobic interactions
Common reactions: N-dealkylation and aromatic hydroxylation

76
Q

Name a CYP3A4 substrate

A

Lidocaine
Tamoxifen
Cocaine
Verapamil

77
Q

What are the big 3 P450 isoforms

A

CYP3A4
CYP3C9
CYP2D6

78
Q

What are the key substrates of CYP2C19

A

Omeprazole and clopidogrel

79
Q

What factors determine metabolism by specific P450 isoforms

A

Topography of active site of enzyme
Degree of steric hindrance of access of Fe-O complex to possible metabolism site
Ease of e- of H+ abstraction from various carbons

80
Q

Where is the CYP1A1 found and what is its role

A

Role: activation of polycyclic aromatic hydrocarbons
Found: mainly outside of the liver

81
Q

What does CYP2E1 contribute too

A

Ethanol metabolism

82
Q

What role does CYP1A2 have

A

Activate arylamine compunds to carcinogens
Role in caffeine metabolism

83
Q

What is involved in non-P450 phase I metabolism oxidation reactions

A

Flavin-linked monooxygenases
Prostaglandin H-synthase-dependent co-oxidation
Amine oxidases
Oxidoreductases

84
Q

What is involved in non-P450 phase I metabolism hydrolysis reactions

A

Esterases
Epoxide hydrolases

85
Q

Describe FMOs

A

Smaller than P450s but have similarities
Require NADPH and O2
Overlap in substrate specificity w P450 -> yield distinct metabolites

86
Q

What are the properties of FMO

A

Oxidise nucleophilic N, P or S centres
Contain FAD as a prosthetic group
All isoforms except FMO5 are non-inducible

87
Q

What enzymes have peroxidase activity

A

Prostaglandin H-synthase
Myeloperoxidase
Lactoperoxidase

88
Q

Describe PGHSs

A

Involve co-oxidation of:
arachidonic acid -> prostaglandin
xenobiotic -> oxidised metabolite

Has cyclooxygenase activity and peroxidase activity and co-oxidation of xenobiotic

89
Q

What is the mechanism for COX activity in PGHSs

A

Arachidonic acid -> PGG2
Oxidation reaction

90
Q

What is the mechanism for peroxidase activity in PGHSs

A

PGG2 -> PGH2
Reduction reaction

91
Q

Describe prostaglandin H-synthase

A

O atom transferred not derived directly from O2
NADPH is not a cofactor

92
Q

Describe MAOs

A

Mitochondrial enzyme which oxidises via FAD-dependent pathway
Main role: metabolism of neurotransmitters

93
Q

What are the 2 forms of MAO

A

MAO A
MAO B
Have different substrate specificities

94
Q

what is the reaction mechanism of MAO

A

RCH2NH2 + FAD -> RCH=NH + FADH2

RCH+NH +H20 -> RCHO + NH3

FADH2 + O2 -> FAD + H2O2

95
Q

Describe oxidoreductases

A

Oxidising: NAD(P) dependent
Reducing: NAD(P)H dependent

Mainly cytosolic enzymes

96
Q

Describe the reaction for alcohol and aldehyde dehydrogenase

A

Alcohol -> aldehyde
RCH02 + NAD+ -> RCHO +NADH +H+

Aldehyde -> carboxylic acid
RCHO + NAD+ -> RCOOH + NADH + H+

97
Q

Describe the normal method of ethanol detoxification

A

Via alcohol dehydrogenase
NAD+ required as a co factor
Converts alcohols -> carbonyls

CYP2E! Uses excess ethanol as a substrate

98
Q

Describe the role of carbonyl reductase

A

Catalyses the reduction of carbonyl compounds in the general form:
R-CHOH-R’ + NADPH <=> R-CO-R’ + NADPH + H+

99
Q

Describe quinone oxidoreductase I

A

2 e- reductase that reduces quinones -> hydroquinones
No semiquinone intermediate = no singlet oxygen

100
Q

Describe carboxylesterases

A

Catalyse the hydrolysis of a wide range of esters, thioesters and amides
Have 2 forms : CE1 and CE2

101
Q

What is the preferred substrate of CE1

A

Small alcohol group, large acyl group

102
Q

What is the preferred substrate of CE2

A

Large alcohol group and a small acyl group

103
Q

Describe butyrylcholinesterase

A

Major contributor to hydrolysis of aspirin to salicylate in plasma

ChE or BChE

104
Q

Describe hCE1 reactions

A

Cocaine -> benzoylecgonine
Heroin -> 6-acetyl morphine -> morphine

105
Q

Describe epoxide hydrolases

A

Cleaves epoxides in the presence of water
2 forms: microsomal and cytosolic -> different substrate specificities

106
Q

Describe paroxonase 1

A

Enzyme w arylestrase, lactonase and paroxonase activities
Role: degradation of oxidises lipids and protects LDL and HDL from lipid peroxidation

107
Q

What happens in phase II metabolism

A

Conjugation reactions
Compounds have greater MW and are more water soluble
Less able to pass through cell membranes = easier to excrete

108
Q

Describe glucuronidation

A

Carried out by UDP-GTs
UDP-glucuronic acid required as co-factor

109
Q

What are the effects of glucuronidation

A

Promotes excretion and results in loss of biological activity Biological activity present in some glucuronides
Some glucuronides are reactive and bind irreversible to proteins

110
Q

Describe the family of UGTs

A

2 distinct families: UGT1 and UGT2
Have different isoforms

111
Q

Describe how UGT1 and UGT2 isoforms are produced

A

UGT1: products of the same gene
UGT2: products of separate genes

112
Q

How are glucuronides conjugates eliminated

A

MW> 400: excreted in the bile
MW< 400: excreted in urine

113
Q

Describe enterohepatic recirculation

A

Beta-glucuonidase produced by the micro flora removes the glucorinde portion of the metabolite
Original drug reformed and re-enters liver via portal vein

114
Q

How does enterohepatic recirculation effect pharmacology of drug

A

Potentiates the activity = increases t1/2

115
Q

Describe the glucuronidation reaction

A

UDP-glucuronic acid reacts w -OH, -COOH, -NH2 and -SH

116
Q

How can UDP-GT be induced

A

Induction is modest compared to CYPs
Family 1: phenobarbitone and PAHs - not UDP-GT specific
Specific inducers operate through the antioxidant response element (ARE)

117
Q

Describe sulfotransferases

A

Catalyse the transfer reaction of sulphate group from PAPS to an acceptor group

118
Q

Why is sulfation useful

A

Sulfate esters are anionic = more soluble
Usually pharmacologically inactive
Lead tor edged availability of drugs

119
Q

Why does sulfation tend to be important at low substrate concentrations

A

Sulfate availability is limited
PAPS is an expensive commodity

120
Q

Why can sulfation be dangerous

A

Can result in activation to carcinogens
Some derivatives are pro-carcinogens and can spontaneously form reactive nitrenium compounds

121
Q

Describe amino acid conjugation

A

Occurs in mitochondria
Proceeds by activation of carboxyl group to its Acetyl CoA derivative
Amide formation w amino group of conjugating amino acid follows

122
Q

What carries out the initial reaction in amino acid conjugation

A

Mitochondrial xenobiotic medium chain fatty acid: CoA ligase (MACS)

123
Q

Why are so few xenobiotics conjugated to amino acids

A

N-acetyl transferase is selective
Not all CoA thioesters formed by MACS are conjugated

124
Q

Describe acetylation

A

Carried out by acetyltransferases
Acetyl CoA donates acetyl group
2 types of human transferases NAT1 and NAT2

125
Q

Where is NAT1 and NAT2 expressed

A

NAT1: most tissues
NAT2: mainly liver and intestines

126
Q

Which NAT is the most polymorphic

A

NAT2 - referred to as polymorphic NAT
NAT1 - referred to as monomorphic NAT

127
Q

What substrates do NATs have

A

Isoniazid (NAT2) and sulfamethoxazole (NAT1)
Restricted number of substrates due to requirement for amino group

128
Q

What are the effects of acetylation

A

Results in masking amine groups w acetylation group = decreased solubility

129
Q

What is glutathione

A

Tripeptide important in maintaining reduced environment within the cell
Can be oxidised during glutathione peroxidase reaction = GS-SG

130
Q

Describe GSTs

A

Mainly soluble;e enzyme that conjugates reduced glutathione to electrophilic compounds through nucleophilic cysteine thiol groups

131
Q

What are the most important forms of GST subfamilies in humans

A

Alpha class
My class
Pi class
Theta class

132
Q

What classes of GST are inducible

A

Alpha and mu
Inducers include: PAHs, barbiturates and antioxidants

133
Q

Describe glutathione conjugation

A

Bonds through nucleophilic cysteine thiol group
Nucleophilic substitution of acetates, sulphate, nitrates and epoxides
Conjugates lose glutamic acid and glycine
Cysteine is N-acetylated to give stable mercapturic derivatives

134
Q

Name a drug substrate of GST

A

Anti cancer drugs
Vasodilators
Analgesics
Diuretic

135
Q

How does methylation and acetylation affect excretion

A

Do not improve solubility
Reduce pharmacological activity instead

136
Q

What are the 3 different methyltransferase families

A

O-methyltrasnferases
N-methyltrasnferases
S-methyltrasnferases

137
Q

What is the co-factor for methyltransferases

A

S-adenosylmethionine (SAM)

138
Q

What is pharmacogenetics

A

The study of unusual responses to drugs and other foreign compounds that have a hereditary basis

139
Q

What is a genetic polymorphism

A

A mutation that occurs at a frequency of at least 1 in every 100 chromosomes
Can be a base substitution, insertion or deletion

140
Q

What is a single nucleotide polymorphism

A

Mutation that occurs 1 in every 1000 bases
Most do not have a functional effect

141
Q

Describe a functional polymorphism

A

Has an effect on biological activity

142
Q

What causes functional polymorphisms

A

Amino acid substitutions
Splice site change
Effect on txn factor binding

143
Q

How does phenotyping analyse genetic polymorphisms

A

Measures enzyme activity directly by:
Giving a probe drug and measuring metabolites
Direct enzyme assay

144
Q

How does genotyping analysis genetic polymorphisms

A

Look directly for presence of mutation in individuals DNA
Need to know gene responsible for defect and what mutation to screen for

145
Q

Why can some patients experience adverse effects if they lack metabolising enzyme

A

Drug has a narrow therapeutic index
Drug is not metabolised by other enzymes

146
Q

Name a few common loss of activity polymorphisms in CYP2D6

A

CYP2D6*3 allele - A deleted

CYP2D6*4 allele - substitution G -> A

CYP2D6*5 allele - entire gene is deleted

147
Q

What copies of genes do poor metabolisers have

A

2 copies of loss of activity in any combination

148
Q

Describe CYP2D6 ultra rapid metabolisers

A

Have an extra copy of the CYP2D6 gene adjacent to the wild type
Results in more enzyme and faster drug metabolism

149
Q

What are the consequences of CYP2D6 polymorphisms

A

Have higher plasma concentrations of certain drugs
Risk of exaggerated effects and toxicity problems
Prodrugs can be ineffective
Poor response to treatment due to fast metabolism

150
Q

describe NAT2

A

NAT2 acetylates a variety of xenobiotics

151
Q

describe the NAT2 polymorphisms

A

People that lack NAT2 activity are called slow acetylators
Have 2 copies of the mutated gene

152
Q

What are the clinical consequences of NAT2 for Isoniazid

A

Slow: more likely to show neurotoxicity and increased risk of hepatotoxicity
Fast: more likely to show lack of response to intermittent therapy

153
Q

How does biotransformation is a major cause of toxicity

A

Direct biotransformation of parent drug to toxic metabolites
Metabolites which are subsequently metabolised to toxic metabolites

154
Q

What can inadequate assessment of metabolism lead to

A

Adverse reactions in trial participants
Drug attrition rates
Drug recall even after approval

155
Q

What is the purpose of reaction phenotyping

A

To identify the specific enzymes responsible for the metabolism of a specific drug

156
Q

Why are primary hepatocytes the gold standard

A

Physiologically relevant model retaining in i i o like functions
Ability to asses whether compound passed through membrane

157
Q

What are the cons of using primary hepatocytes

A

Limited by suitable liver sources
Immediate cryopreservation is important
Can lose functionality if cultured over a long period of time

158
Q

Why are microsomes used in experiments

A

Can be derived from any organ
Cryopreserved without loss of function
Genotyped

159
Q

How to calculate the amount of drug excreted

A

Amount excreted = amount filtered - amount reabsorbed + amount secreted

160
Q

What does it mean if the drug is filtered in the nephron

A

Left untouched by the nephron
Amount excreted = amount filtered

161
Q

What does it mean if the drug is filtered then reabsorbed by the nephron

A

Amount excreted < amount filtered

162
Q

What does it mean if a drug is filtered and secreted by the nephron

A

Amount excreted > amount filtered

163
Q

How to calculate total renal clearance

A

Cl by filtration + Cl by secretion - retention by reabsorption

164
Q

When does the renal function not affect the elimination of an active compound

A

When the active drug is metabolised mainly to inactive metabolites

165
Q

When does the renal function effect the elimination of an active compound

A

The active drug and/or metabolites excreted in the kidneys

166
Q

What drugs do not enter the filtrate

A

Macromolecules e.g heparin

167
Q

What happens to the clearance if the drug is bound to plasma proteins

A

Conc of drug in filtrate = free unbound drug
Clearance by filtration is reduced

168
Q

How to calculate the rate of clearance

A

Filtration is directly proportional to GFR (120ml/min) and the fraction of unbound drug in plasma (Fu)
Clr = Fu x GFR

169
Q

When can Clr = Fu x GFR be used

A

When a drug is principally cleared by filtration
Can be affected by secretion and reabsorption

170
Q

What happens if Clr < Fu x GFR

A

Renal absorption is taking place
Clr is significantly affected by changes in urine flow

171
Q

What is the principal factor in the passive tubular reabsorption of weak acids and bases

A

The pH of the renal tubular fluid
Ionisation and passive reabsorption dependent on pH in relation to pKa of drug

172
Q

What happens to the reabsorption rate if a drug is ionised

A

Decreased

173
Q

What happens to the reabsorption rate if a drug is unionised

A

Reabsorption will be higher
Unionised form can diffuse through the proximal tubule cell membrane

174
Q

Name 2 independent non selective carrier systems

A

Acidic drugs and endogenous compounds
Organic bases

175
Q

Describe drug-drug interactions in the proximal tubule

A

Drug 2 is a better substrate for effluent than drug 1
They compete for the pump when administered together
Drug 1 accumulates to toxic concentrations

176
Q

Name an acid that is actively secreted into the renal tubule

A

Glucuronic acid conjugates
Uric acid
Salicylic acid
Penicillins

177
Q

Name a base that is actively secreted into the renal tubule

A

Dopamine
Histamine
Morphine
Serotonin
Amiloride

178
Q

What drugs cause hyperuricaemia

A

Diuretics and low dose aspirin

179
Q

What is a first line therapy for gout

A

Allopurinol

180
Q

How does age affect drug metabolising enzyme levels

A

Levels are low
Unable to clear the drugs as effectively
Can lead to toxic build up

181
Q

Describe the changing levels of CYP1A2 from neonatal to toddler

A

Neonatal: undetectable
1–3 months: present at low levels
<1 year: approx 50% of adult value
3+ years: comparable to levels in adults

182
Q

How can the difference in species affect metabolism

A

Phase I: different metabolites produced from same drug
Phase II: variation in conjugation of sulphate and glucuronic acid to substrates
Variation in proportion of phenol conjugated to glucuronide and sulfate

183
Q

What other issues are there in using animals for metabolising experiments

A

Different strains show differences in metabolism due to genetic differences

184
Q

Why are there difference in metabolism between rat species

A

Differences in expression patterns of CYP2A, CYP2B, CYP2C and CYP3A enzymes

185
Q

What are the consequences of using rats to study metabolism

A

Each isoform has a different specificity so different metabolism patterns between sexes

186
Q

What effect do growth hormones have on CYPS within rats

A

Specific effect on CYP2C enzymes in sex-related manner
Levels increase at puberty and up regulate expression of different CYPs

Pharmacology (2 decks)

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