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CXPT 610 > Lecture 3/4: Intro to Drug Metabolism > Flashcards

Lecture 3/4: Intro to Drug Metabolism Flashcards

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1
Q

Why are large molecule drugs not generally safe?

A

due to pk/pd

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2
Q

Why might the pd for small molecules might not work?

A

it depends on the target and whether it localizes to it

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3
Q

What is pharamcokinetics?

A

the activity or fate of drugs in the body over a period of time including the processes of absorption, distribution, localization in tissues, biotransformation and excretion - what the body does to the drug

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4
Q

What is pharmacodynamics?

A

the study of the biochemical and physiological effects of drugs and the mechanisms of their actions including the correlation of action and effects of drugs with their chemical structure also the relationship between drug concentration and effect - what the drug does to the body

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5
Q

What is delivery?

A

a drug engages into a receptor or enzyme target and the amount of drug that gets to the target site aka the localization of the drug

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6
Q

What is exposure?

A

the measure for the amount of drug that an organism has really seen

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7
Q

What is bioavailability? What are some varaibles in bioavaliability?

A

a measure for the proportion of the dose that reaches the systemic circulation and is not the same as exposure
-variables in bioavailability - can have the placebo effect, difference between male and female, ethnicity, diet/lifestyle

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8
Q

What is clearance?

A

a measure of the elimination of a compound from the blood given as volume cleared/time
-(how much drug gets out of the body; kids have good clearance since they have a fast HR and cause they have smaller blood volume so it is easier to circulate)

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9
Q

What is the volume of distribution?

A

a measure of the theoretical volume that a compound distributes to
-to (in chemo patients blood vessels can break and the volume expands)(want to take into consideration height and weight like bmi but this is not great so you can look at fat free mass instead)

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10
Q

What is the unbound fraction?

A

the fraction of drug not bound to proteins - C unbound = fu x Ctotal (we have differin albumin levels it is typically 4.4 but varies)

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11
Q

What is the half life?

A

a measure of the time it takes for the organism to decrease the concentration of the drug by 50%
- (changes, want to study not after one administration of drug but at steady state concentrations because the conc. Does not change)

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12
Q

What is cmax?

A

maximum concentration of drug at that dose
-maximum amount going in is going to equal the maximum amount going out

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13
Q

When a drug is infused what is the rate of the uptake?

A

it is rapid

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14
Q

When there is a steep curve down on an AUC what does that mean?

A

the drug is being distributed to tissues

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15
Q

What is the AUC and how is it calculated?

A

by trapezoids
total drug exposure in the blood over time

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16
Q

If rat plasma concentration of BAY XX-XXXX after oral administration of 5mg/kg how do you convert this to human?

A

-in order to convert this drug conc to human you divide by 6 for humans and multiple by 70 - this is good drug for humans cause the conc is 50-100mg for humans which is sub 500 mg - any drug above 500mg can have off target effects - most drugs today are 10mg which means they are highly specific and they rarely have off target effects and ven if they do not much will happen
-the drug in the graph has a long half life so that tells you that the orally administered drug is absorbed throughout the gi tract

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17
Q

What is the lipinski rule of 5?

A

its ability to be absorbed into the bloodstream when taken by mouth)

MW < 500 daltons
-no more than 5 h bond donors
-no more than 10 H bond acceptors
-calculated logP value (measure of lipophilicity) less than 5 Log P is the logarithm of a compound’s partition coefficient (P), which measures how a substance distributes between a hydrophobic (oil-like) phase and a hydrophilic (water-like) phase. It’s calculated as:
P=[Concentration in octanol]/[Concentration in water]

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18
Q

On average what percent of drug gets from free circulation to tissue?

A

4-10%

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19
Q

What is a common toxic metabolite and why?

A

anything that makes an aldehyde
-can make a protein-protein aduct haptin-repeat aduct of a protein reacts with arginine cause arginine has a primary amine which allows reaction - if a haptin occurs get an immunological response - aka vaccine or immunogen and can cause drug allergies - amoxicillin does this because it has a reactive beta lactone which can cause a rash allergy

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20
Q

What is included in pharmacokinetics?

A

dose —> absorption —> plasma (can be free or protein bound)—> elimination (metabolism or renal excretion)

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21
Q

What is included in pharmacodynamics?

A

most tissues nonspecific binding —-> distribution —> biophase receptor binding —-> effect

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22
Q

What are some factors that lead to interindividual variation in drug plasma concentrations?

A

genetics
age
gender
tissue differences
route of administration
other factors
-co administered substrates - inhibitor or inducers
-autoinduction - inducing the synthesis of liver enzymes which speed up its metabolism
-diet
-disease - hepatic or renal
-protein binding

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23
Q

How are xenobiotics eliminated?

A

metabolism (biotransformation to enhance water solubility)
excretion - secreting xenobiotics or its metabolites

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24
Q

What is the role of cyp450 mediate metabolism and p glycoprotein interaction and its influence on absorption?

A

what is the purpose of cyp450s - to help with the secretion of hormones aka endobiotics in the body
-the isoforms present in the body changes of cyp450s with puberty and steroids you might tale
-estrogen is neuroprotective so women below 60 do not get many diseases
-drugs get dissolved in acid media in stomach the ph here is 1 or 2
-when drugs enter the small intestine the ph is 6.1-7.5
-drug also needs to be resistant to peptidases in the small intestine
-the blood is the basolateral side
-the lumen of the intestine is the apical side
-endocytosis or transporters can push the drug out of the lumen to reduce exposure

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25
What are the types of xenobiotics biotransformation?
–how does the body sense is something is toxic -if anything is unchanged going from portal vein to hepatocyte to excretion the it is water soluble -anything lipophilic is a signal for the body to metabolize it PXR and XXR are transcriptional signals on metabolic enzymes and efflux transporters -very fatty body hydroxylated and allows for conjugation and then excretion -can carboxylate something to increase water solubility
26
What are the main routes by which drugs and their metabolites leave the body?
-kidney -hepatobilliary system -lungs -skin -most drugs leave the body in the urine either uncharged or as polar metabolites -some drugs are secreted into the bile via the liver -but most are reabsorbed from the intestine
27
Hoe are peptide drugs eliminated?
via peptidases
28
What does dna or rna break down into?
urea or uric acid
29
What is a general overview of what occurs for the metabolism of a lipophilic drug?
phase i - increase chemical reactivity -oxidation reduction hydrolysis -mediated by cyp450 phase ii - conjugation with polar group - glucuronidation, sulfation, glutathione -mediated by transferases excretion --> urine or bile drug changes from lipophilic to moderately hydrophillic to hydrophillic
30
What do the nuclear receptor genes do PXR, CAR, FXR?
they are biomarkers and they control the expression of efflux transporters and metabolic enzymes -phase i enzymes - i.e. cyps phase 2 enzymes like UGTs and sulfation
31
What is metabolism?
the chemical transformation of xenobiotics occurs mostly in the liver - through enzymatic processes -conversion into more hydrophillic substrates - excretion urine -may convert pro carcinogen into cytotoxic mutagenic compounds - want to put it into oocytes and then do an aims test and see do it affect my ability to reproduce does it cause mutagenesis -take the compound and put it into hepatocytes cause we do not know what cyp450 isoform works -different persons may have different metabolism - genetic difference and physiology factors - sick vs healthy metabolism changes -metabolism of one xenobiotic may influence metabolism of another
32
What are the pathways of metabolism in terms of phases?
phase i: biotransformation - attachment of new functional groups or transformation of existing functional groups - oxidation, reduction, hydroxylation, hydrolysis etc - phase ii: conjugation - masking of an existing functional group by acetylation, glyoslyation, attachment of amino acid etc -essentially want to make the drug more hydrophillic and prepare it for renal excretion
33
What are some of the types of metabolic enzymes?
CYP 450 - system NAD FAD - very high in kids to detoxify o2 - have a heme group get o2 converted by nadph esterases - most abundant enzyme in body different isoform in tissues amidases monoamine oxidases - get rid of catecholamines, metabolizes nts
34
What are some medications and their role?
-erythropoietin - rc production -scrape the bulb if poppy seed plant and get opium → morphine -willow bark aspirin -statin - block cholesterol production comes from red yeast -codeine cough medicine -same as morphine but take off hydroxyl on benzene ring
35
What is the structural diversity of CYP 450 and what is it due to?
the structural diversity is due to non specificity and there are isoenzymes - or multiple forms of an enzyme
36
Are cyp450 enzymes inducible?
yes by various chemicals - expsure increases the rate of enzyme production
37
How are cyp450 enzymes isolated?
through disruption of liver cells -the ER releases microsomes when disrupted
38
Are cyp450 enzymes membrane bound, and what is there catalytic process?
yes they are membane bound -they explain why lipophillic drugs are processed and their catalytic process involves the heme binding to O2
39
What does cyp1a2 breakdown?
caffeine
40
What does cyp2d6 breakdown?
morphine - hydrophobic brain drugs
41
What does cyp3a4 breakdown?
most drugs
42
What can happen if a drug is fatty?
it can insert itself into the membrane of cells and and change the membrane permeability -need to look at the PQ interval on an EKG to make the heart rate does not slow too much due to drug - to make sure this does not affect the conduction of the heart
43
What kind of family of enzymes are cyp enzymes involved in?
a super family with a very broad substrate selectivity
44
What is cyp nomenclature based on?
shared homology of amino acid sequence - there are currently 17 families and over 50 isoforms identified in the human genome
45
What are the CYP families?
CYP plus an arabic numeral and they share an amino acid sequence homology of greater than 40% - i.e. CYP1
46
What is the cyp450 subfamily?
40-55% homology of amino acid sequence - i.e. CYP1A
47
If more than one subfamily has been identified what is added?
an additional arabic numeral
48
What does italics indicate versus regular font?
italics indicates the gene and regular font for actual enzyme
49
What does high serotonin cause?
dry eyes
50
What percent of cyp enzymes is 3a4/5/7, 1a2, and 2d6?
30% 15% 5%
51
If you have the gene for an enzyme does it mean you express it?
not always - expression an be deoendent on diet and lifestyle
52
What percent of drugs are primarily metabolized by CYPs?
60%
53
What percent does cyp3a and 2d6 contribute to drug metabolism?
3a-40-50% 2d6 -30%
54
What phase ii enzyme contributes the most to drug metabolism?
UGTs
55
What catalyzed phase i oxidatuve reactions and where are they found, what are their specificities, and are they polymorphic?
multigene family of hemaprotein monooxygenases -are membrane bound and found in smooth er -broad and overlapping specificities -polymorphic in human population
56
What type of enzymes catalyze phase ii reactions?
transferases
57
How much does the MW of a compound increase by with glucuronidation?
176
58
How much does the molecular weight of a compound increase by with sulfation?
80
59
How much does the molecular weight of a compound increase by with gluathione?
305
60
What determines the levels of cyp450?
hormones - endogenous role of the enzymes is to metabolize these - they are located in the smooth er in all tissues
61
What induces p450 expression?
PPAR ligands - peroxisome proliferator activated receptor (ligand example is clofibrate)
62
What is the CYP1 family expression induced by>
aromatic hydrocarbons
63
What is the CYP2E enzymes induced by?
ethanol
64
What is the CYP2B enzymes induced by?
40-50 fold by barbituates
65
What does the CYP2c19 polymorphism cause?
changes the ability of the enzyme to metabolize mephenytoin a marker drug -in caucasians this polymorphism for the poor metabolizer phenotype is only seen in 3% of the population -it is seen 20% of the asian population (it is important to be aware of a persons race when you are giving drugs)
66
DME and transporter are under the regulation of transcriptional factors what are some of these factors?
PXR and CAR and FXR are a family of transcriptional factors that regulated the expression of the dme and transporters -together with rxr these transcriptional factors regulate the expression of these proteins
67
What is CAR?
constitutive androstein receptor which is androgen
68
What is PXR?
PXR is a pregame xenobiotic receptor or steroid xenobiotic receptor
69
Are CAR and PXR co receptors?
yes
70
What are the repressors for CAR and PXR? How are they displaced?
hsp90 and ccrp -when anything fatty binds to them they are displaced
71
What does aldoketoreductase AKR1b7 do?
gets rid of aldehyde
72
What is the coactivator for CAR and PXR?
RXR
73
In summary how are xenobiotic receptors like PXR and CAR activated?
through the displacement of repressors via hydrophobic compounds -the competition between repressor and substrate will activate PXR -activation of pxr will allow it to heterodimerize with RXR and translocate into the nucleus and induce protein transcirption -more fatty food you eat more likely you activate this by displacing the repressors - so drugs which induce cyp450 are fatty drugs i.e. refactin (looks like steroids)
74
When you are young why does cholesterol go up?
to drive hormonal production
75
What is the overall regulation of cyp and transporter expression?
small lipophillic molecule ---> nuclear receptor ----> responsive genes
76
What is an example of cyp3a regulation
a fatty drug such as rifampicin, pcn, dexamethasone, ru486, clotrimazole, troglitazone, or tamoxifen can displace the repressors on pxr and allow it to go into the nucleus and bind to the xenobiotic response elements and induce the transcirption of cyp3a enzymes in the liver and intestine (since pxr is expressed in lver and intestine) -cyp3a will then hydroxylate xenobiotics and endobiotics -Anything fatty activates pxr and car cause it to displaces repressor hsp90 and ccrp and cause transcription of cyp3a -diverse drugs activate through a heterodimer complex -protect against xenobiotics -cause ddi
77
What does atorvastatin accumulation cause?
-atorvastatin accumulation causes raptomyolysis aka muscle breakdown
78
What are some fatty drugs that need to be hydroxylated by cyp3a?
ethunylestradiol, erthromycin atorvastatin indinavir efavirenz cyclosporin carbamazepine warfarin tamixofen doxorubicin
79
What is gastroinetstinal regulation of cyp and transporter expression?
Hiv drugs are very fatty and comes in and displaces the repressor and there is an rxr and this up regulates cyp450 and pgp and this reduces the drug going from enterocytes into the blood can induce this in the intestine - take drug and get diarrhea the first three days very likely it causes these effects due to the body seeing it as foreign - every cell has pgp
80
What are pxr/sxr ligands?
ensogenous loigands are bile acids like lithocholic acid steorid ligand - pregnane, pregnenolone, dexamethasone, ru486 -antibiotics - rifampicin herbal products - hyperforin
81
If you inject testosterone into a person what will happen?
their pxr will go up
82
What is PXR more specifically?
-one of the nuclear receptor family of ligand activated transcription factors -named on the basis of activation by natural and synthetic c21 steroids known as pregnanes including pregnenolone 16a-carbonitrile -cloned due to homology with other nuclear receptors -highly active in the liver and intestine -binds as a heterodimer with RXR
83
What is CAR more specifically?
highly expressed in liver and intestine -sequestered in the cytoplasm - cofactor is pxr and rxr -co factor complex required for activation anchored by PPAR binding protein PBP -binds response elements as RXR heterodimer -high basal transcriptional activity without ligand -activated by xenobiotics - phenobarbital, TCPOBOP
84
Do PXR and CAR regulate overlapping genes?
yes phase i enzymes - cyp3a11, cyp2b10, aldh1a1, aldh1a7 phase ii enzymes - ugt1a1, gsta1 transporters - mrp2,mrp3, oatp2
85
What is FXR and its ligand?
faneosid x receptor ligands - bile acids
86
What tissues are PXR, CAR, and FXR found in?
PXR - liver, kidney, small intestine, colon CAR - liver, intestine, heart, kidney, lung FXR - liver, kidney, small intestine, colon
87
What are the ligands for PXR, CAR, and FXR?
PXR - rifampin, PCN, clotrimazole, RU486, nifedipine, hyperforin CAR - TCPOBOP, PB, Androstanol FXR - bile acids
88
What are the target genes for pxr, car, and fxr?
pxr - cyp3a4/7, 2b6, 2c9mdr/pgp, mrp2 car - cyp 2b6, 3a4, 2c9, mrp2, mdr1/pgp, ugt1a1 fxr - spgp, ntcp, mrp2, dhea sulfotransferase
89
How does fluoridation at different positions affect lipophilicity of a compound?
FLUORINATE AT ORTHO CAN INCREASE STERICS AND LIPOPHILICTY SO STICKS AROUND LONGER FLUORINATE AT PARA CAN INCREASES LIPOHILICTY SO STICKS AROUND LONGER FLUORINATE AT META - NOT AS FAT SOLUBLE -ALTERS ELECTRON DENSITY OF THE RING AND CAN REDUCE BINDIN AFFINITY SO MIGHT NOT BIND AS WELL TO RECEPTOR CAN BE EXCRETED MORE QUICKLY —PARA IS BEST IN REGARDS TO LIPOPHILICTY -ORTHO NEXT DUE TO STERICS -META NOT MUCH OF AN EFFECT SO LAST
90
What is an inhibitor of pgp?
grapefruit
91
What drug can induce intestinal pgp?
rifamycin
92
What does pxr and car do?
activate the transcription of phase i and ii enzyme and transporters
93
What are abc transporters?
pgp, mdr1, mrp1, mrp2, cMOAT, MOAT-d, moat-b, moat-c, moat-e, bcrp, mrp3, mrp4,5,6, mxr, abc-p
94
Where do enterocytes pump into?
pump into lumen of gi tract
95
Where do hepatocytes pump into?
bile
96
Where do renal tubular cells pump into?
pump out into lumen of proximal tubule
97
What tend to be the substrates of sodium independent exchange transporters?
substrates tend to be amphipathic molecules with high molecular weight >450 HCO3=, glutathione, GS-conjugates
98
How can pgp be induced by protease inhibitors?
-pxr mediated regulations are inducible -pxr mediated transcription of pgp an efflux transporter is inducible via exposure and time of exposure -rifampin and st johns wort
99
What is the effect of ritonavir on sxr?
cause start to increase the concentration up regulate the sxr
100
What is fxr activated by?
bile acids -bilirubin breaks down into bile acid to liver to gall bladder
101
What is a reaction phenotyping method for calculating intrinsic clearance?
intrinsic clearance is the enzyme mediated clearance that would occur without physiological limitations (hepatic blood flow) rate of metabolism v = vmax *Ce/Km + Ce CLint = vmax/km when Ce << Km C = C0 * e^-kt t1/2 = ln2/k CLint = ln2/ t1/2 * [HLM]
102
How do you scale intrinsic clearance to in vivo hepatic clearance?
initial rate / half-life/k (hepatocyte/tissue/microsomes/s9)---> CLint(in vitro) scaling factors ----> CLint in vivo ---model of hepatic clearance----> CLh as %QH in vivo clearance
103
What is significant inhibition deemed as?
>80% decrease in HLM turnover/rate/intrinsic clearance) clearly signifies a primary metabolic clearance pathway
104
For the example of reaction-phenotyping - mirtazapine?
the predominant form is the demethylation - and what enzyme does this - predominantly 3a4 but could be a mix of them so it is reasonable guess - FDA is a 90% correlation need to map it out to prove
105
What are first pass effects?
-once a xenobiotic is absorbed across the intestinal wall the blood enters into the liver for potential elimination via hepatic metabolism -in the liver compounds can be highly extracted which is dependent on solubility and concentration -in the liver excretion can occur via excretion into the bile duct and into the intestines - the compound can also be metabolized via hepatic enzymes
106
What is reversible metabolism via enteroheptic cycling?
Liver extracts it and pumps it out into the larger intestines and gets metabolized by bacteria in the gut and remove the glucose via glucoronidase and get reabsorbed -it absorbed unchanged meaning it is gluconridated - bacteria in gut can ungluconridate and reabsorb it through the enter hepatic circulation- for bile intact rats - how much goes from blood to liver and liver to bile to fecal matter - drug goes out in the bile and blood concentration goes up- there is glucoronidase in the bacteria of the gut and can cleave off the glucoronide and get reabsorbed
107
Where does bile go after it is produced by the liver?
the liver does not send bile directly to the large intestine. The liver produces bile, which is stored in the gallbladder. When food, especially fatty food, enters the small intestine, the gallbladder releases bile into the duodenum (the first part of the small intestine) through the common bile duct. Bile helps to break down fats into smaller molecules so they can be absorbed. After the small intestine has absorbed most nutrients, any leftover bile can pass into the large intestine, but it’s not a primary route for bile flow.
108
How long does enteroheptic cycling take?
enterohepatic cycling or recirculation takes four to eight hours cause it takes that long to get down to the large intestine and get reabsorbed
109
What are some ways you can inhibit enteroheptic cycling?
elimination of gut bacterial flora -inhibiting beta glucuronidase in the intestine -binding metabolite excreted in the bile - cholestyramine, charcoal
110
When looking at reversible metabolism via in vivo cleavage - particularly the deconjugation of acyl glucuronides in systemic circulation?
-acyl glucuronides are labile once produced and exposed to hydrolases in vivo -pmsf and other nonspecific esterases have been shown to inhibit this cleavage -the unproductive conjugation increases exposure to the [arent drug in vivo
111
How can valproic acid glucuronide cleavage be inhibited?
bu carbapenem blocking hydrolytic enzymes
112
How do you dose a drug?
2-3 times a half life -protein drugs are once a month and antibodies last 24 days
113
What clearance does the FDA want?
85-95% clearance
114
Does UGT supress CYP3a4 activity?
yes
115

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