Drug – Drug Interaction and Drug Transporters : What ‘ s new ? J.M.SCHERRMANN Club Phase 1 Meeting, Paris, 22 March 2016
Drug – Drug Interaction and Drug Transporters :
What ‘ s new ?
J.M.SCHERRMANN
Club Phase 1 Meeting, Paris, 22 March 2016
FROM WHERE DO WE COME?
TRANSPORTERS and PHARMACOKINETICS in 1987Michael SCHWENK : Review, Drug Transport in intestine, liver and kidney.
Arch. Toxicol. 60, 37, 1987
"Drug transport in the intestine
occurs mainly by diffusion"....
" Intestinal drug carriers
contribution seems to be of minor
importance."
"The liver is the organ where
carrier-mediated drug transport
predominates"
ENZYMES and PHARMACOKINETICS
in 1987
« Genetic polymorphism of human
cytochrome P450 (S)-mephenytoin 4-
hydroxylase (P-450 meph)
(U.T. MEIER and U.A. MEYER, 1987) »
« Metabolism of cyclosporin A. Interaction
of erythromycin, using rabbit hepatocytes
and microsome fractions
(P-450 LM3c or P-450IIIA4)
I. FABRE et al. (J.P. CANO), 1988
TRANSPORTERS and PHARMACOKINETICS
in 1987Michael SCHWENK : Review, Drug Transport in intestine, liver and
kidney. Arch. Toxicol. 60, 37, 1987
Four hypothetical carrier systems for
hepatocellular drug uptake
Carrier 1 Carrier 2 Carrier3 Carrier4
Bile acids
Estronesulfate
Estradiol
glucuronide
Bilirubin
Bromosulphophtalein
ANS
Indocyanine green
Morphine
NalorphineOuabain
"bile acid carrier" "organic anions" "organic cations"
OATPs
NTCP
OATPs
NTCP
OCT1, 3 OATPs
DIFFUSIONAL versus VECTORIAL PHARMACOKINETICS
X
CYPs
CEs
X-OC
X
X-OH
X-OC
D
A
E
Ante 2000
« Diffusional PK »
Passive
Diffusion
Passive
Diffusion?
M
XXX
CYPs
CEsX-OH
Post 2000
« Vectorial PK »
Active
Efflux
Active
Influx
Active
Efflux
Passive
Diffusion
X
Phase 0
Phase I
Phase II
Phase III
X-OC
X-OC
1st period : cancer research (1970 - )
MDR (Multi Drug Resistance) phenotype
( Juliano and Ling , 1976 )
MDR1, P-glycoprotein, ABCB1
Mdr1a et Mdr1b in rodentscavéoline
2nd period : pharmacology (1990 - )
Expression in healthy tissues (Protection and
Detoxification , the << GATEKEEPER >> )
1st PK-Pgp study published by Tsuji and Terasaki in
1992 (Life Sci.51, 1427,1992 )
3rd period : Guidance for Industry (2006 - )
substrate/inhibitor identification
P-GLYCOPROTEIN : PIONEER and LEADER
Aller et al., Science
2009,323:1718‐1722.
70 Å
~13
6 Å
~30
Å
WHERE WE ARE TODAY ?
• ABC (ATP Binding Cassette) SUPERFAMILY48 human genes; ≈ 9 drug transporters
SUPERFAMILIES and FAMILIES of DRUG TRANSPORTERS
• SLC (SoLute Carrier) SUPERFAMILY
> 362 mammalian genes; ≈ 30 drug transporters
« 15% of human genes code for 4500 transport proteins »
Paulsen, FEBS Lett., 1998 ; J. Mol. Biol., 1998
EFFLUX (Conjugated Metabolites)
EFFLUX (Xenobiotics(MDR, Tissue Defense)
SECONDARY (TERTIARY) ACTIVE TRANSPORTERS
ABC Superfamily
PRIMARY ACTIVE TRANSPORTERS
S
ATP
S
ATP
S ABCCS
ABCB, ABCG
GSH
INFLUX and/or EFFLUX(Xenobiotics, Conjugated Metabolites)
SLC Superfamily
1
2
S S
3
H+
H+
K+
Na+
ABC and SLC TRANSPORTERS
P-glycoprotein, ABCB1, MDR1
Breast Cancer Resistance Protein (BCRP, ABCG2)
MRPs, Multi-Drug resistance associated Proteins
OATs Organic Anion T.OATPs Organic Anion Polypeptide T.OCTs Organic Cation T.
Membrane Transporters
in Drug Development:
Giacomini et al., Nature Rev
Drug Disc 2010
White Paper 2010
ABC Transporters
P-gp
BCRP
BSEP
MRP2
MRP3
MRP4
MDR3
International Transporter Consortium in 2007
White Paper 2010
SLC TransportersOATP1B1
OAT1
OATP1B3
OAT3
OCT2
OATP1A2
OATP2B1
OCT1
PEPT1
PEPT2
MATE1
MATE2
Membrane Transporters
in Drug Development:
Giacomini et al., Nature Rev
Drug Disc 2010
P-gp/BCRP Inhibition Tree
High Solubility Low Solubility
HighPermeability
Class 1(High Solubility, High
Permeability)Metabolism
”High hepatic extraction”Transporter effects
minimal
Class 2(Low Solubility, High
Permeability)
MetabolismEfflux transporter effects
predominate
LowPermeability
Class 3(High Solubility, Low
Permeability)
Renal and/or BiliaryElimination
Absorptive transporter effects predominate
Class 4(Low Solubility, Low
Permeability)
Renal and/or BiliaryElimination
Absorptive and efflux transporter effects could be
important
The Biopharmaceutics Classification System and transporters
From G. Amidon , Pharm. Res, 12, 413, 1995 and C.Y. Wu , Pharm Res, 22, 11, 2005
INTESTINE(enterocyte)
FECESORALEXPOSURE SecretionAbsorption
LIVER(hepatocyte)
BILE
Efflux
Uptake
Excretion
BBB(brain microcapillary
endothelial cell)
Efflux Uptake
BRAIN
KIDNEY(tubuleproximal cell)
URINE
Secretion
Reabsorption
Filtration
From JM SCHERRMANN-Comprehensive Med.Chem, 2007
PHARMACOKINETIC ROLE OF TRANSPORTERS
Drugs as substrate, inhibitor or regulator?
TRANSPORTER PROTEIN
INHIBITION
MDR Reversal
TRANSPORT
SUBSTRATE
EXPRESSION
( Induction or Repression of Regulation PathwaysGenetic Polymorphisms)
And Candidates for DDI ?
INTESTINAL LUMEN
SYSTEMIC BLOOD
;;
basolateral
membrane
Apical
(brush border)
membrane
MRP5 MRP4 MRP3 OCT1 MCT1
MRP2 BCRP MDR1 OATP1A2
OATP2B1
OATP3A1
OATP4A1
MCT1PEPT1
IMPACT OF TRANSPORTERS ON DRUG ABSORPTION
FRUIT JUICE, A GLASS FULL OF DRUG INTERACTIONS
F Fexofenadine (57 %), Talinolol (44 %), Celiprolol (87 %)
CYP3A4
OATP1A2
ABCB1
!
IC50 5 M
IC50 3000 M
GRAPE FRUIT JUICE
Naringin
ORANGE FRUIT JUICE
Hesperidin
COMPETITIVE
INHIBITION GRAPE FRUIT JUICE
Bergamottin6,7-dihydroxybergamottin
MECHANISM-BASED
INHIBITION
From DG Bailey et al, CPT, 81, 2007
BIOAVAILABILITY OF FEXOFENADINE
Influence of delay betweengrapefruit juice and fexofenadine intake
4h
+ 2h (37%)
0h (57%)
F
From H. Glaeser, Clin. Pharmacol. Ther., 2007
Traditional Chinese Medicine and Transport Interactions
Herb Active compounds Transporter target DDI risks Ref
Rhubarb AnthraquinonesOAT1OAT3
(kidney)
YesInhibition
Ma LJ.Ethnopharmacol
2014
Turmeric (Curcuma longa)
Curcumin
ABCA1ABCB1ABCC1ABCG2
Inhibition (MDR
reversal)
Zhang X Front. Physiol 2014
DanshenRosmarinic acid
Tanshinol Lithospermic acid
OAT1OAT3
(kidney)
Yes Inhibition
Wang L Drug Metab
Pharmacokinet. 2013
Huang-Qin-Tang MultipleMCT1
(intestine and BBB)
Yes Inhibition
Yu CP Phytomedicine
2013
Yanhusuo (YHS) glaucineABCB1ABCC1
Yes Inhibition
(MDR reversal)
Lei Y Food Chem 2013
BLOOD
IMPACT OF TRANSPORTERS ON DRUG AT THE HEPATO-BILIARY
LEVEL
From JM SCHERRMANN-Comprehensive Med.Chem, 2007
UPTAKE
Phase 0
EFFLUX
Phase 3a
EFFLUX
Phase 3b
DRUG INTERACTIONS MEDIATED BY TRANSPORTERS
From W. Muck, Clin Pharmacol Ther, 65, 251, 1999
CERIVASTATIN (0.2 mg/d)-CYCLOSPORINE (400mg/d)
in kidney transplant recipients
Myopathy and Rhabdomyolysis
AUC X 5
SIROLIMUS AUCX3
TACROLIMUS AUCX 1,3
PgpCsA
CsA (Ki≈0,2µM)
Cerivastatin
OATP1B1
CsA
(IC50 ≈30µM)
CYP3A bile
SNP
c521T>C
Atorvastatin
OATP1B1
Link et al, NEJM 2010
Effect
Rhabdomyolysis (OR 16)
HEPATIC UPTAKE AND BILIARY EXCRETION OF
VALSARTAN
(angiotensin II AT1-receptor antagonist)Valsartan
Absorption (F ≈ 30-50%)Faecal excretion ≈ 85% (bile)Vss ≈ 17 LClt ≈ 2,2 L/ht1/2 ≈ 7h
From W. Yamashiro et al, Drug Metab Dispo. 2006
UPTAKE
Phase 0
EFFLUX
Phase 3a
BCRPMDR1 MRP4-5
OATP1A2URAT1
OCTN2
MRP1-2-3-5-6 ?OAT3
BLOOD
BRAIN
luminal
membrane
abluminal
membrane
tight
junctions
Transporter-mediated Drug Interactions at BBBIMPACT OF TRANSPORTERS ON DRUG DISTRIBUTION
BLOOD-BRAIN BARRIER
MCT1
MCT1
P-Glycoprotein and Breast Cancer Resistance Protein :
Two Dominant Transport Working Together in
Limiting the Brain Penetration of Topotecan
N.A. de Vries, Clin Cancer Res, 2007
3.20.652.0Brain/
Plasma
1.61.5AUC
Brain/WT
3.72.40.75AUC
Plasma/WT
Bcrp1(-/-)
Mdr 1a/1b (-/-)
Bcrp1(-/-)Mdr1a/1b(-/-)
12
Topotecan IV 5 mg/kg
« Synergistic Effect of P-gp and BCRP
on common substrates »
Erlotinib, Gefitinib, Lapatinib, Imatinib
Flavopiridol, Mitoxantrone, Prazosin
IMAGING P-GLYCOPROTEIN TRANSPORT ACTIVITY AT THE HUMAN BBB WITH PET
Magnetic
resonance image
11C-Verapamil
Control + CSA
L. Sasongko et al,
CPT, 2005
J. Bart, NeuroImage, 2003
CSA
50µg/kg
0
Basolateral
membrane
OCTN1- 2
OAT2
Apical
membrane
URAT1
OAT4
OATP4C1
OAT 1- 3
MRP1- 3- 5- 6
MDR1, BCRP
MRP2- 4
OCT 1-2- 3
PEPT1- 2
SAT1OATP1A2
IMPACT OF TRANSPORTERS ON DRUG ELIMINATION
RENAL LEVEL
From JM SCHERRMANN-Comprehensive Med.Chem, 2007
BLOOD URINE
MATE1
V ≈ 25 L
fup = 0,97
t1/2 6- 10h
Clr (# 100Clt)
Clr =250 ml/min
activité
extracellulaire
Nature 438, 3 novembre 2005
Phosphate
d’Oseltamivir
(Tamiflu®)
Estérases Carboxylate
d’Oseltamivirneuraminidases
(virus grippal)
PK PD
Wartime tactic doubles power of scarce bird-flu drug
Nature 438, 3 novembre 2005
Transporter-mediated Drug Interactions: OAT1, SLC22A1
Renal tubules
OAT1
Wartime tactic doubles power of scarce bird-flu drug
PBN
Transporter-mediated Drug Interactions at Kidney
From Koepsell and Endou, Eur J Physiol, 447, 666, 2004
DDI : Salicylate-methotrexate
(1000 mg) (2.5 mg)
MATE1
Paraquat, 1-methyl-4-phenyl
pyridinium (MPP+)
Lee W.K, Curr Drug Metab 2009
Pralidoxime, (Antidote of
organophosphate)
Renal secretion mediated by OCT1/2
Kayouka M, Crit Care Med, 2011
QUESTIONS ?
(I) In vitro - in vivo correlation
R = fold systemic AUC change (≈ CYP-based drug interactions)
Cl
Cl
AUC(inhibitor) 1R= = 1
fAUC
fu I1+ +1-f
Ki
Ki = in vitro inhibition constant
[I] = inhibitor plasma concentration
fu = unbound plasma fraction
fcl = fraction of the total clearance mediated by the affected transporter
Cl
Iif f =1 R=1+fu (2)
Ki
Question : Quantitative Prediction of in vivo Drug Interaction?
DRUG INTERACTIONS MEDIATED BY TRANSPORTERS
(I) In vitro - in vivo correlation
From CJ. Endres, Eur J Pharm Sci 27, 501, 2006
IAUCR=
AUC
fcl
DRUG INTERACTIONS MEDIATED BY TRANSPORTERS
(II) Quantitative prediction of in vivo drug interaction
From C.J. Endres, Eur J Pharm Sci, 27, 501, 2006
K.Ball et al., AAPS J., 2013
Question : Interspecies differences in Transporter Expression
ABC and SLC differences between species in brain microvessels
ABC differences between in vivo / in vitro BBB (hCMEC/D3)
MDR1
BCRP
MRP1
MRP4
MRP5
0.001
0.01
0.1
1
10
100
Relative expressionin hCMEC/D3compared to
human brain microvessels
S.Dauchy et al.,Biochem. Pharmacol., 2009
Relative to human
brain microvessels
Question : Are in vitro models reproducing the in vivo conditions
P-gp Efflux Ratio for Opioids
N. Tournier, Curr Pharm Design, 2011
11.3
Question : role of active metabolites ?
• Impact of Quantitative Proteomic MS-MS
on transportome atlas -the Terasaki Dream –
• From single transfected cell models to quadruple transfectedsystems – J. König –
• Computational prospecting for drug-transporter Interactions
• Development of non-invasive technologies including imaging
• Ontogeny in the expression and localization of transporters indifferent tissues
• Establish clinically important transporter polymorphisms
• Intracellular concentrations: measurement modeling implications for the liver
Questions : Many others……
WHERE IN ADME ?
TM
A
D E
EFFECT
PD
« Transport and Metabolism are Effectors of the time course of
Drug Absorption, Distribution, and Elimination »
FROM ADME TO ADE ?
THE ADE-TM triangles :
F
CltVd
JM Scherrmann, Chem. Biodiv. 6 (2009)