the importance of concept of fraction of drug transported ...intestinal transport . nedmdg 6 ? oatp...

1

Department of Pharmaceutics School of Pharmacy University of Washington Seattle, WA

http://sop.washington.edu/department-of-pharmaceutics/faculty-members/

Jashvant (Jash) D. Unadkat, Ph.D.

NEDMDG

The Importance of Concept of Fraction of Drug Transported (ft) in Understanding and

Predicting Drug Disposition and DDI

NEDMDG 2

Tissue/Membrane Localization of Drug Transporters

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Unadkat JD, Enzyme-and Transporter-Based Drug-Drug Interactions: 2010.

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OATP1B1

OATP1B3

MATE1

NTCPOCT1

UrinePEPT

1,2 OAT4

MATE1,2

OCTN1,2

OAT1,3

OATP4C1 OCT2

Kidney

BBB

Brain Interstitial Space

Blood

P-gp BCRP

Cerebrospinal Fluid

BCSFB

Fetal blood

MRP 1,2,4,5BCRPP-gp

MRP 1,4

MRP 1,3,4,5,6

P-gpBCRP

MRP2MRP2,4

BCRPP-gp

P-gpBCRPMRP2

MRP2Liver BCRP BSEPP-gp

OATP2B1

OATP1A2

OATP3A1

OAT3

MRP1,3,5

MRP1,3,5,6

Bile

2B1

/2B1

NEDMDG 3

When a significant fraction of the drug dose is absorbed, distributed into an eliminating or non-eliminating tissue, or cleared from the body via transporters (i.e. ft is large) Modulation of the transporter(s) by DDI or SNPs will NOT affect exposure of the tissue to the drug (i.e. AUC) if the drug is cleared primarily through that organ/tissue. However the Cmax and Cmin in the tissue will be affected. NOT significantly affect the systemic CL of the drug If the fraction of the dose distributing into a tissue via a transporter is small But, will have a profound impact on the tissue concentration and therefore potentially the toxicity and efficacy of the drug – disconnect between the plasma and tissue conc.

ft will determine the impact of transporter DDI or SNPs on systemic or tissue conc. of drugs

When are Transporters Relevant to ADME?

NEDMDG 4

When a new molecular entity is found to be a substrate of a transporter, consider the following : Is the transporter(s) present in the tissue of interest? If so, what is its contribution relative to CLdiffusion and CLother transporters? In vitro transport ≠ in vivo relevance because transfected cell lines (or X. oocytes) often exaggerate ft due to high expression of the transporter A substrate can be a potent inhibitor of a transporter without being a substrate Even if the affinity of the substrate for the transporter is low and the expression of the transporter in the tissue of interest is low, that transporter could still be important in determining the clearance and/or tissue conc. of the drug if ft via that transporter is large. ft is king!

Some Principles

NEDMDG 5

I.V. or S.C.

Oral Dose

Brain

Blood

Proximal Tubule

Renal Artery

Blood

Maternal Blood

Syncytiotrophoblast

Urinary Excretion

Liver

Gut Wall

Gut Lumen

Fecal Excretion

Bile Duct

Portal Vein

Endres et al., Eur J. Pharm. Sci., 2005

Illustration of these Principles Via a Magic School Bus Tour Through the Body

Intestinal Transport

NEDMDG 6

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OATP1B1

OATP1B3

MATE1

NTCPOCT1

UrinePEPT

1,2 OAT4

MATE1,2

OCTN1,2

OAT1,3

OATP4C1 OCT2

Kidney

BBB


Blood

P-gp BCRP

Cerebrospinal Fluid

BCSFB

Fetal blood

MRP 1,2,4,5BCRPP-gp

MRP 1,4

MRP 1,3,4,5,6

P-gpBCRP

MRP2MRP2,4

BCRPP-gp

P-gpBCRPMRP2


OATP2B1

OATP1A2

OATP3A1

OAT3

MRP1,3,5

MRP1,3,5,6

Bile

2B1

/2B1


NEDMDG 7 PCEUT527

Absorption : Transport can be Rate-limiting Step(s) in Bioavailability of Drugs

fraction absorbed (fa) via transporters >> fraction absorbed (fa) via passive diffusion (BDDCS class 3 & 4)

Benet, J Pharm Sci, 2012

[D]

Intestinal Lumen BloodEnterocyte

[D]

[D]

[D]

[D]

[D]

X

[D] [D]X[D]

[M]

[M]

[M]

dual rate-limiting steps for class 3 & 4 drugs – apical and basal membrane

NEDMDG 8

Concentrative Nucleoside Transporter 2 Limits the Intestinal Absorption of Ribavirin (ft=~0.8)

Moss et al., Mol. Pharm. 2012

Na+

-Na+

Vectorial Transport

Ribavirin CNT2

ENT1

NEDMDG 9

Ribavirin Concentration in Intestinal Tissue of mEnt1(-/-) and Wild Type Mice

20 uM 200 uM 5 mM

Rib

av

irin

Co

nc

en

tra

tio

n (µ

M)

Do

se N

orm

aliz

ed

to

20

µM

0.000.050.100.150.200.250.300.35

1.00

2.00

3.00

4.00

5.00

6.00

Wild Type mEnt1(-/-)

**

***

*** **

***

Equilibrative Nucleoside Transporter 1 (ENT1) Limits the Egress of Ribavirin from the Intestine to the Blood

Moss et al., Mol. Pharm. 2012

Green Tea-Nadolol DDI – OATP1A2?

NEDMDG 10

AUC 85%

Misaka Clin Pharmacol Ther. 2014 Apr;95(4):432-8.

OATP1A2?

[D]

Intestinal Lumen Blood Enterocyte

[D] [D]

NEDMDG 11

Nadolol is transported by OATP1A2 but not by OATP2B1

OATP1A2 HEK293 cells

NEDMDG 12

Drozdzik et al., Mol Pharm. 2014 Oct 6;11(10):3547-55

But, OATP1A2 mRNA or protein was not detected in human intestinal tissue! This DDI must be due to some other

mechanism(s)

For IVIVE and mechanism of DDI, important to ask if the transporter is PRESENT in the tissue of interest

NEDMDG 13

When a drug is found, in vitro, to be a substrate of a transporter, ask: Is the transporter present in the tissue of interest? What is the contribution of this transporter relative to diffusion or other transporters, i.e. what is ft for each transporter? In specialized cells (e.g. enterocytes), transporters can pose dual rate-limiting steps (apical and basal) in bioavailability or clearance of drugs Inhibition of efflux transporters (e.g. at the basal membrane) can profoundly increase the local tissue conc. and therefore potential toxicity of the drug

Summary

NEDMDG 14


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?

OATP1B1

OATP1B3

MATE1

NTCPOCT1

UrinePEPT

1,2 OAT4

MATE1,2

OCTN1,2

OAT1,3

OATP4C1 OCT2

Kidney

BBB


Blood

P-gp BCRP

Cerebrospinal Fluid

BCSFB

Fetal blood

MRP 1,2,4,5BCRPP-gp

MRP 1,4

MRP 1,3,4,5,6

P-gpBCRP

MRP2MRP2,4

BCRPP-gp

P-gpBCRPMRP2


OATP2B1

OATP1A2

OATP3A1

OAT3

MRP1,3,5

MRP1,3,5,6

Bile

2B1

/2B1

• Parallel Routes of Elimination • Metabolic (CLint)

• Canalicular Efflux (CLcef)

• Bi-Directional Hepatic Distribution • Sinusoidal Influx (CLsin)

• Sinusoidal Efflux (CLsef)

• Diffusion

Bile MATE1

OATP 1B1

OATP 1B3/2B1

NTCP OCT1

Blood

MRP 1,3,4,5,6

MRP2

Liver

BCRP BSEP

P-gp

CYP

Parent Metabolite CLint

CLcef

CLsin/ef

Revisit and Modify Hepatic Clearance Concepts to Include Transporters

NEDMDG 15

Key Assumptions Ignore Transporters or Permeability Limitations : •The transfer from perfusate to the liver is instantaneous and not limited by permeability • Unbound drug concentration in the plasma and the liver are the same

Hepatic Well-Stirred Model

Perrier, D. and Gibaldi, M. ,J. Pharmacol. Exp. Ther., 191 (1974) Wilkinson, G.R and Shand, D.G. Clin Pharmacol Ther. 18 (1975)

int

int

L u

L u

Q f CLCLQ f CL

×=

+QL, Cin

Clint

VR

VL

Reservior

Liver

QL, Cout

NEDMDG 16

QL, Cin

Clint

VR

VL

Reservior

Liver

QL, Cout

NEDMDG 17

Modification of the Well Stirred Model to Include Transporters

Endres et al., Mol Pharm. 2009 6:1756-65

( ) ( ) ( )( )( ) ( )( )sefcefLcefsinu

cef

sinu

sef

cefOtherL

cefOther

sinu

CLCLCLQCLCLCLfCLCLCLfCLCLCLCLQCLCLCLCLf

++++

++++++

intint

intintint

When CLother = 0 ( )( ) ( )( )sefcefLcefsinu

cef

sinLu

CLCLCLQCLCLCLfCLCLCLQf

++++

+

intint

int

and when CLsef ≈ 0 or

Clsin

Clsef

Dependence of Systemic Clearance on Sinusoidal Permeability of the Drug

0.1 1 10 100

0.1

1

10

100

When CLsin is low or

(In)Dependence of Systemic Clearance (CL) on CLint and CLcef Clearances

0.1 1 10 100 Clsin

Clsef 0.1

1

10

100

NEDMDG 20

Assumptions: CLother = 0 QL=1 (arbitrary vol/time units); Fp/FL = 1

When sinusoidal distributional CL is 100-fold QL (=1), then Clsys is limited by QL . When CLsin is

As CLsin ↑, systemic CL ↑, AUC reservoir ↓

BUT AUC liver ↔

As CLint ↑, systemic CL↔,

AUC reservoir ↔, BUT AUC liver ↓

When CLsin is

Changes in ALL clearance pathways WILL affect systemic AND liver

AUC

22

CLother = 0.4; CLint =0.3, Clcef =0

When Clsef is not 0

( )( ) ( )( ) othersefcefLcefsinu

cef

sinLu

sys CLCLCLCLQCLCLCLfCLCLCLQf

CL +++++

+=

intint

int

NEDMDG 23 23

Hepatic OATPs limit Systemic CL of Atorvastatin: Rifmapin DDI

7-fold ↑

2.7-fold ↑

Bile Blood [D] [D]

Met

CYP

Lau et al., 81, 2007

X

11C-Rosuvastatin – Rifampin DDI in the Rat

Blood

24

11C-Rosuvastatin blood conc. –time profile

NEDMDG

Bile Blood

[D]

[D]

[M]

Hepatocyte

OATPs

He et al., Mol Pharm. 2014

Hepatic Uptake and Biliary Excretion of 11C-Rosuvastatin in the Rat

Coronal 2 min SUV images of 11C-Rosuvastatin

Mol Pharm., ‘14

Bile Blood

ROS

Hepatocyte

OATPs BCRP/MRP2

-RIF +RIF

25 He et al., Mol Pharm. 2014

NEDMDG

26

NEDMDG

Blood

+RIF

-RIF

27

11C-Rosuvastatin blood conc. –time profile

AUCR0-15min (AUCRIF/AUCcontrol) ↑ 230%

Liver

11C-Rosuvastatin hepatic conc. –time profile

AUCR0-15min 5% ↑

NEDMDG

11C-Rosuvastatin – Rifampin DDI in the Rat

He et al., Mol Pharm. 2014 OATPs

Bile Blood

ROS

Hepatocyte

BCRP/MRP2

NEDMDG 28

Hepatic transporter(s): What is the contribution of the transporter relative to diffusion or other transporters, i.e. what is ft for each transporter? If the uptake transport is a concentrative, it may be the rate-limiting step. Modulation of this transport (e.g. DDI, SNPs) may profoundly affect the systemic conc. of the drug. But, the impact on hepatic conc. is likely to be much smaller because:

• dX/dthepatic uptake = CLuptake remainder x Cp,u and Cp,u is ↑ • If the drug is mostly cleared by hepatic CL, it will eventually be eliminated by passage through the liver

Inhibition of efflux transporters (e.g. MRP2) can profoundly increase the hepatic conc. and therefore potential toxicity/efficacy of the drug

Summary

NEDMDG 29


?


?

OATP1B1

OATP1B3

MATE1

NTCPOCT1

UrinePEPT

1,2 OAT4

MATE1,2

OCTN1,2

OAT1,3

OATP4C1 OCT2

Kidney

BBB


Blood

P-gp BCRP

Cerebrospinal Fluid

BCSFB

Fetal blood

MRP 1,2,4,5BCRPP-gp

MRP 1,4

MRP 1,3,4,5,6

P-gpBCRP

MRP2MRP2,4

BCRPP-gp

P-gpBCRPMRP2


OATP2B1

OATP1A2

OATP3A1

OAT3

MRP1,3,5

MRP1,3,5,6

Bile

2B1

/2B1

NEDMDG 30 30

Sasongko et al (2005) Clin Pharmacol Ther. 77:503-514. Muzi et al J Nucl Med, 2009 Eyal et al., Clin Pharmacol Ther. 2010

P-gp Transport of 11C-verapamil at the Human BBB and Inhibition by Cyclosporine A (CsA)

11C-verapamil

CsA infusion (2.5 mg/kg/hr) for 60 min

Time

~45 min

15O-water

11C-CO

~45 min 12 min 15 min 15 min

11C-verapamil 15O-water

Continue CsA infusion for ~45 min

31

Plasma and Brain 11C-verapamil radioactivity concentration-time profiles in the absence and

presence of CsA

Time (min)

0 10 20 30 40 50

Plas

ma

11C

-rad

ioac

tivity

/ D

ose

(L-1

)

0.01

0.1

Plasma

- CsA + CsA

Sasongko et al (2005) Clin Pharmacol Ther. 77:503-514.

Time (min)

0 10 20 30 40 50

Bra

in 1

1 C-r

adio

activ

ity /

Dos

e (L

-1)

0.01+ CsA - CsA

Brain

↑~2-fold

NEDMDG

Effect of CsA different than that in rodents: 87% vs. 1000%

NEDMDG 32

What is the ft of verapamil? Can the effect of maximal inhibition of P-gp be discerned from our data?

Cb, cerebellum FC, frontal cortex OC, occipital cortex Pu, putamen PI, pituitary T, thalamus V, lateral ventricle

A

B C

D E F

T

FC FC FC

OC OC OC

V V

C C

C

Pu Pu

T T CP CP CP

Pi Pi Pi

Cb Cb Cb

V

V V V

B C FC FC FC

C Pu

-CsA +CsA Eyal et al., Clin Pharmacol Ther. 2010

NEDMDG 33

Regional 0-10 min brain distribution of [11C]-radioactivity

0.00

0.05

0.10

0.15

0.20

Whi

te m

atte

r

Gre

y m

atte

r

Thal

amus

LT c

orte

x

Fron

tal c

orte

x

Cer

ebel

lum

Occ

ipita

l cor

tex

Par

ieta

l cor

tex

Put

amen

Cau

date

Before cyclosporineDuring cyclosporine

0.0

0.1

0.2

0.3

0.4

0.5

Late

ral t

empo

ral

corte

xLa

tera

l tem

pora

l co

rtex

K1

of 11

C-r

adio

activ

ity (m

L/m

in/g

)

a

Cho

roid

ple

xus

Pitu

itary

b

b

b

b

a

K1

of 11

C-r

adio

activ

ity (m

L/m

in/g

)

a

Cho

roid

ple

xus

Pitu

itary

b

b

b

b

a

0.00

0.05

0.10

0.15

0.20

Whi

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Gre

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x

Fron

tal c

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l cor

tex

Par

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tex

Put

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date


0.0

0.1

0.2

0.3

0.4

0.5

Late

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corte

xLa

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l tem

pora

l co

rtex

K1

of 11

C-r

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in/g

)

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Pitu

itary

b

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K1

of 11

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itary

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Late

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L/m

in/g

)

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Pitu

itary

b

b

b

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K1

of 11

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L/m

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Pitu

itary

b

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K1

of 11

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in/g

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itary

b

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of 11

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Pitu

itary

b

b

b

b

a

Eyal et al., Clin Pharmacol Ther. 2010

ATP

ADP + Pi

Brain

Blood

NEDMDG 34

ft of [11C]-Verapamil radioactivity is ~0.8 in humans and macaques

•Based on these data, the MAXIMUM increase (on complete inhibition of P-gp) in verapamil distribution into the human brain is predicted to be ~4-5 fold • confirmed by studies in nonhuman primates, the macaque

Eyal et al., Clin Pharmacol Ther. 2010

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0.0

0.1

0.2

0.3

0.4

0.5

Whi

te m

atte

r

Gre

y m

atte

r

Thal

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LT c

orte

x

Fron

tal c

orte

x

Cer

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lum

Occ

ipita

l cor

tex

Par

ieta

l cor

tex

Put

amen

Cau

date


Ext

ract

ion

ratio

Pitu

itary

Cho

roid

ple

xus

Late

ral t

empo

ral

corte

x

a

bb

bb

a

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0.0

0.1

0.2

0.3

0.4

0.5

Whi

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0.0

0.1

0.2

0.3

0.4

0.5

Whi

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Ext

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a

bb

bb

a

Ext

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Late

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x

a

bb

bb

a

Human

Ke et al., J Nucl. Med. 2013

CsA concentration (µM)

0 5 10 15 20 25 30

Per

cent

incr

ease

in E

R

0

100

200

300

400

500

600Macaque

NEDMDG 35

Substrates Brain to Blood Ratio mdr1(-/)/mdr1(+/+) ft(P-gp)

Nelfinavir 40 Very High (~ 0.975)

Verapamil 9.5 High

(~ 0.9)

Cetirizine (Zyrtec®) 2.3 Intermediate

(~ 0.6)

ft and P-gp DDI at the Mouse BBB

NEDMDG 36

Magnitude of P-gp based DDI at the

Human BBB Depends on f t(P-gp)

of the P-gp substrate

Hsiao et al., Mol. Pharm. 2014

NEDMDG 37

ft and apparent P-gp/BCRP synergism

Blood

Brain Interstitial Fluid

Brain Endothelial Cell P-gp BCRP

CLpgp CLbcrp CLdif

Diffusion

All values are for unbound drug and are arbitrary

ft = 0.95 due to efflux by P-gp and BCRP ftP-gp = 0.475, ftBCRP = 0.475 ftdif= 0.05

• Cssb/Cssp= CLdif/CLefflux = 0.05 • when CLPgp=0, Cssb/Cssp= 0.095 • when CLBCRP=0, Cssb/Cssp = 0.095 ~ 2-fold ↑ when CLPgp+CLBCRP=0, Cssb/Cssp = 1 (~20-fold ↑)

NEDMDG 38

BBB transporter(s): For high ft drugs (>0.9, via P-gp, BCRP or both), there is

potential for inadvertent DDI at the human BBB to be clinically significant if these drugs have a narrow therapeutic window

• Dual inhibition of both P-gp and BCRP could result in a profound increase in brain conc. – but its not synergism, its just ft!

• To estimate the maximum liability for P-gp-based drug interactions that a NME will produce (perpetrator), I propose that rodent studies be conducted with nelfinavir as the substrate and the NME as the inhibitor.

• To estimate the maximum liability for P-gp based drug interactions that a NME will be subjected to (i.e. victim), I propose that the ft(P-gp) of the NME be determined in rodents. Then, the maximum DDI be computed.

Summary

NEDMDG 39

When a significant fraction of the drug dose is absorbed, distributed into an eliminating or non-eliminating tissue, or cleared from the body via transporters (i.e. ft is large) If the fraction of the dose distributing into a tissue via a transporter is small, modulation (e.g. DDI) of this transporter by DDI or SNPs will NOT significantly affect the systemic CL of the drug BUT, if the drug is cleared primarily through that organ/tissue, the AUC in the tissue will not be affected, but the Cmax will be if the drug is NOT cleared primarily through that organ, it will have a profound impact on the tissue concentration and therefore potentially the toxicity and efficacy of the drug – disconnect between the plasma and tissue conc.

ft will determine the impact of transporter DDI or SNPs on systemic or tissue conc. of drugs

Transporters can serve dual rate-limiting step in the absorption or clearance of drugs

.

Overall Summary: When are Transporters Relevant to ADME?

NEDMDG 40

Use primary cells and selective inhibitors But primary cells are not available for many organs (e.g. BBB or intestine) Alternative approach is to use quantitative proteomics and transfected cell lines .

How Does One Determine ft?

ATP ADP + Pi

• Goal is to quantify the expression of transporters (and interindividual variability) in various human tissues using LC/MS/MS

• Funded by a consortium: Merck & Co, Genentech, Biogen Idec (and Astra Zeneca)

• http://sop.washington.edu/department-of-pharmaceutics/research-affiliate-program-on-transporters-uwrapt/

University of Washington Research Affiliate Program on Transporters

ATP ADP + Pi

Relative Transporter Abundance Pie Chart

41 Li et al. DMD 2015 NEDMDG

ATP ADP + Pi

Transporter Expression in Human Intestines

ABCB18% ABCC2 10%

ABCC3 7%ABCG2 4%

ASBT 6%OCT1

8%

OCT31%

OATP2B16%

PEPT1 50%

ABCB15%

ABCC2 25%

ABCC3 36%ABCG2 3%

OCT1 12%

OCT3 2%OATP2B1

12%

PEPT15%

small intestine colon

Relative contribution

42

OATP1A2 could not be detected in the small intestine

N=6, 5 males, 1 female;

NEDMDG

Bhagwat Prasad Anand Deo

43

YuYang Jiake He

Major Contributors

Vineet Kumar Gabriela Patilea Chris Endres and Aaron Moss

Li Wang

NEDMDG

44

Peng Hsiao Huixia Zhang Anita

Mathias Li Liu

Brain Kirby Alice Ke

Aaron Moss Dale Whittington

Mary Blonski Andrew Bostrom

Christina Shadle

Eun Woo Lee Raj

Govindarajan Francisco Chung

Joseph Zolnerciks

VaishaliDixit Amal Kaddoumi

Anshul Gupta Yurong

Lai

Sara Eyal Suresh Naraharisett

Xiaohui Wu Alexandra Vulpanovici

Andrei Mikheev

Alexander Odinecs

Lucy Sasongko

Unadkat Team

Chris Endres NEDMDG

Jiake He, Bhagwat Prasad, Vineet Kumar, Gabriela Patelia

44

NEDMDG 45

Other Collaborators Dept. of Radiology: Jeanne Link, David Mankoff, Todd Richards, Janet Eary, Satoshi Minoshima, Ken Maravilla, Mark Muzi, Steve Shoner and the PET suite team Dept. of Medicine: Ann Collier and her team Dept. of Psychiatry: Soo Borson & Mary Lessig Dept. of Anesthesiology: Karen Domino Acknowledgement: NIH MH63641, P50 HD44404, RR 00166, HD47892, AG031485, RC1NS068904

Univ. of WA Health Sciences

NEDMDG 46

Slide Number 1Tissue/Membrane Localization of Drug TransportersSlide Number 3Slide Number 4Slide Number 5 Intestinal TransportAbsorption : Transport can be Rate-limiting Step(s) in Bioavailability of DrugsSlide Number 8Slide Number 9Green Tea-Nadolol DDI – OATP1A2?Slide Number 11Slide Number 12Slide Number 13Tissue/Membrane Localization of Drug TransportersRevisit and Modify Hepatic Clearance Concepts to Include TransportersHepatic Well-Stirred Model�Modification of the Well Stirred Model to Include TransportersModified Clearance Concepts Slide Number 19Slide Number 20�As CLsin ↑, systemic CL ↑, AUC reservoir ↓ BUT�AUC liver ↔��As CLint ↑, systemic CL↔, �AUC reservoir ↔, BUT AUC liver ↓Changes in ALL clearance pathways WILL affect systemic AND liver AUCHepatic OATPs limit Systemic CL of Atorvastatin: Rifmapin DDI �Slide Number 24Hepatic Uptake and Biliary Excretion of 11C-Rosuvastatin in the RatSlide Number 26Slide Number 27Slide Number 28Tissue/Membrane Localization of Drug TransportersSlide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36ft and apparent P-gp/BCRP synergismSlide Number 38Slide Number 39Slide Number 40Relative Transporter Abundance Pie ChartSlide Number 42Slide Number 43Slide Number 44Slide Number 45Univ. of WA Health Sciences

the importance of concept of fraction of drug transported ...intestinal transport . nedmdg 6 ? oatp...

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