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PCEUT 532 > Midterm #3 > Flashcards

Midterm #3 Flashcards

1
Q

Definition of Bioavailability

A
  • Amount of unchanged drug reaching systemic circulation
  • F=bioavailable dose/administered dose
  • describes extent to which drug is absorbed
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2
Q

How to Measure Oral Bioavailability

A

F=(AUCoral/AUCiv)*(Div/Doral)

AUCoral=(F*Doral)/CL

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3
Q

Absolute vs Relative Bioavailability

A
  • Absolute: oral AUC vs. IV AUC
  • Relative: two oral formulation AUC
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4
Q

Measuring BA using Urinary Excretion Data

A
  • Ae, iv=feDiv
  • Ae,o=feDoF
  • F=(Ae,o/Ae, iv)=(Ae,o/fe*D)
  • Only applies to drugs with 30% or greater fe
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5
Q

Absorption Extent vs. Absorption Rate

A
  • Extent: how much reaches systemic circulation
    • absolute bioavailability (F)
    • measured by (AUC/D), Aetotal, Cmax
  • Rate: how fast
    • ​ka or t1/2 absorption
    • change in these affects Tmax and Cmax, may not affect extent (F, AUC)
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6
Q

Effect of Doubling Dose on Cmax and AUC

A

Double dose, double AUC and Cmax

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7
Q

Effect of decreasing F on Cmax and AUC

A

Decrease F, decrease Cmax and AUC proportionally

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8
Q

Effect of decreasing Ka of Tmax and Cmax

A

increases Tmax and decreases Cmax

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9
Q

Factors Affecting Oral Drug Absorption

A
  • Dissolution
  • Membrane Permeability
  • First Pass metabolism
  • Intestinal efflux and influx transporters
  • Drug stability in GI tract
  • GI physiology
  • Food and other medications
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10
Q

Dissolution Effect on Oral Absorption

A
  • depend on solubility, exciptient, formulation
  • affects dissolution
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11
Q

Membrane Permeability Effect of Oral Absorption

A
  • affects intestinal absorption
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12
Q

First Pass Metabolism Effect of Oral Absorption

A
  • Affects intestinal absorption and liver first pass
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13
Q

Follow Pathway of Drug

A
  • green=dissolution
  • yellow=membrane permeability
  • blue=efflux/influx transporters
  • purple=drug stabilty
  • pink=GI physiology
  • gray=food and other meds
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14
Q

Effect of Formualtion

A
  • Rate Tablet Dissintegration
    • Tablet compression, excipients
  • Rate of Dissolution
    • particle size
    • drug solubility
  • Modified Release
    • reduce frequency of admin
    • deliver drug to site of action
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15
Q

Food and Oral Drug Absorption

A
  • Delays gastric emptying
  • Gastric secretion
  • Bile salt secretion
  • Bind Ca2+, reduces absorption
  • Can interact with enzymes or transporter
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16
Q

Food and Acid Sensitive Drugs

A
  • decreases Abs
  • decreases Cmax
  • decreases F
  • Take 30-60 min before food
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17
Q

Brand Name Drugs

A
  • A new drug (new chemical entity)
  • Approved by FDA under New Drug Applications (NDAs)
  • Marketed by the pharmaceutical company under a branded name
  • Protected by patents for certain years
  • Expensive
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18
Q

Generic Drugs

A
  • Same active drug (chemical entity) as the brand name drug but sold under a different name (often the chemical name of the active drug)
  • Approved by FDA under Abbreviated New Drug Applications (ANDAs)
  • Cost-saving
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19
Q

1906 Pure Food and Drug Act

A

established regulation of Food and Drugs.

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20
Q

1938 Federal Food, Drug and Cosmetic (FFD&C) Act

A

introduced safety standards.

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21
Q

1962 Kefauver-Harris Amendment to the FFD&C Act

A

tightened safety standards and introduced requirement that drugs must be effective.

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22
Q

1984 Hatch-Waxman Act

A
  • created an abbreviated mechanism (ANDA) for approval of generic versions of brand-name drugs without conducting costly and duplicative pre-clinical and clinical testing.
  • increased availability of generics, greatly reduced the cost of prescription drugs
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23
Q

Bioequivalence replaces these 3 things in ANDA

A

clinical studies, animal studies, bioavailabilty

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24
Q

generic drug definition

A
  • drug product that is comparable to brand/reference listed drug product in:
    • dosage form
    • strength
    • route of administration
    • quality and performance characteristics
    • intended use
25
Q

Pharmaceutical Equivalence

A
  • Same active ingredients
  • Same route of admin
  • Same dosage form
  • Same strength
26
Q

Labeling

A

Same conditions of use

27
Q

Therapeutic Equivalence

A
  • Same performance characteristices
    • efficacy and saftey
28
Q

Pharmaceutical Alternative

A

different salts, esters, dosage form or strength, also ER vs. IR

29
Q

Therapeutic Interchange

A

drugs in the same therapeutic class (Atorvastatin vs. Simvistatin)

30
Q

Does PE=TE

A
  • NO!
  • TE=BE+PE
31
Q

Two products are bioequivalent if

A
  • They are pharmaceutically equivalent
  • Systemic absorption (both rate and extent) after administration are not significantly different
32
Q

BE Testing, Key PK parameters

A
  • Compare Cmax and total exposure
33
Q
  • e.g. drug with very long half-life (e.g. amiodarone)
  • e.g. drugs with highly variable PK
  • e.g. pt trials and ER/IR
  • e.g. topicals, nasal drugs
A
  • Single-dose parallel design
  • Single-dose, replicate design
  • Multiple-dose, two-way crossover
  • Clinical endpoint study
34
Q

Absorption, Distribution and Elimination barriers

A
  • Absorption:
    • Oral: Small intestine mucosal layer
    • Topical: Skin: Stratum Corneum
    • Intranasal: Nasal Membrane
  • Distribution:
    • BBB
    • placenta
  • Elimination:
    • Kidney Secretion: proximal tubule epithelium
    • Hepatobiliary Secretion: hepatocyte membrane
35
Q

Paracellular Transport

A
  • indepent of size, charge, lipophilicity
  • not for protein bound
  • pore transport/filtration
36
Q

Fick’s First Law of Diffusion

A
  • Jc=P*SA*(Cu1-Cu2)
  • Jc=rate of diffusion (mg/min)
  • P=permeability (cm/sec)
37
Q

Permeability Coefficient

A
  • P=(K*D)/delta x
  • K=partition coefficient depending on **hydrophobiticity **and charge
  • D=diffusion coefficient depending on size and membrane viscosity
  • delta x: membrane thickness
38
Q

too lipophilic and too polar

A
  • too lipophilic:
    • insoluable, bind plasma protein
  • too polar
    • not get though gut wall or BBB
39
Q

Lipinski Rule of 5

A
  • Poor Abs/Permeability when:
    • MW>500
    • LogP>5
    • 5 H-bond donors
    • 10 H-bond acceptors
  • Exceptions: substrates relying on drug transporters
40
Q

Ionization

41
Q

pH Partition Hypothesis

A
  • only unionized get into equilibrium at membrane
  • total concentration on each side depends on ionization degree
    • greater iniozation, greater total C
42
Q

Characteristics of Carrier-Mediated Transport

A
  • specific, inhibitable, saturable
43
Q

MM equation

A
  • V=(Vmax*S)/(Km+S)
44
Q

SLC Transporters

A
  • OATPs, OAT, OCT
  • Gene: SLC(family #) A (member #)
  • Protein: related to function
  • Exception: SLCO family (OATP)
45
Q

ABC Transporters

A
  • P-gp, MDR
  • Gene: ABC (family letter)(member #)
  • Protein: Reflects function
46
Q

Importance of Drug Transporters

A
  • determinant of drug disposition and response
  • DDI
  • Inter-individual intervariability
  • Source for non-linear kinetics
47
Q

P-gp

A
  • efflux transporter
  • part of ABC family
  • lipophilic, cationic, nuetral, bulky rings
  • substrates are ampipathic, MW >400kDa. positive charge at pH 7.4
  • inhibited by clarithromycin
  • induction of P-gp by rifampin decreases oral absorption
  • Pumps drugs back into intestine lumen, decrease oral absorption
  • facilitate bilary secretion
  • faciitatie renal recretion
  • prevent drug into brain
  • preven drug into placenta
48
Q

Drug Elimination in Liver and Drug Transporters

49
Q

OATPs

A
  • 1b1, 1b3, 2b in liver
  • sinusidol side of liver
  • drug uptake into liver
  • Eliminate statins
  • cyclosporin inhibit 1b1
    • create 10 fold increase in AUC of statin…myopathies
50
Q

First Approach to Determining Renal Clearance

A
  • blood and urine collection over several t1/2
  • CLr=(Ae/D)*CL=feCL
51
Q

Second Approach to Determining Renal Clearance

A
  • urine collection over short period and blood collection at midpoint
  • CLr=(dA/dt)/Cmid
52
Q

Renal Clearance from these 3 process

A
  1. Glomerular Filtration
  2. Tubular Secretion
  3. Tubular Reabsorption
  • Rate Exrection=(1-FR)(Rate of Filtration + Rate Secretion)
    • FR=fraction reabsorbed from lumen
53
Q

Glomerular Filtration

A
  • 120 mL/min
  • urine flow 1-2 mL/min
  • Rate Filtration=GFR*Cu=GFR*fu*C
  • Renal Extraction Ratio (E)=CLr/Qr=(120 mL/min)/1200=0.1
  • glomerular filtration is a low efficiency process
54
Q

CLr

A
  • CLr=(fu*GFR)+CLsecretion-CLreabsorption
  • CLfiltration=fu*GFR
  • if CLr>CLfiltration, net secretion
  • if CLr<cl>filtration,net reabsorption</cl>
55
Q

Organic Kidney Anion Secretion

A

OAT1/3, MRP, OATP

56
Q

Organic Kidney Cation Secretin

A

OCT2 and MATE-1

57
Q

OCT2, OATP1/3, and P-gp in renal tubular cells

A
  • OCT2 and OATP1/3: from blood to cell
  • P-gp: from cell to urine
58
Q

OAT1/3 inhibitor, interactions

A
  • probenecid
  • interacts with beta-lactams, NSAID, diuretics, antiviral, etc.
  • transport anionic drugs
59
Q

OCT2 inhibitor and interactions

A
  • interact wtih cations
    • metformin, H2 blockers, endogenous calcium
  • ​​inhibited by cimetidine

PCEUT 532 (1 decks)

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