James Med chem Mod 6

stomach pH

 

 

 

Intestine pH

stomach pH: 2-6

 

 

 

Intestine pH: 6-8

Most rx absorption in
small intestine
Passive must be

less than 4 angstroms

 

less than 200 molecular weight

Log S is the solubility in water
Log S greater than -4 is soluble in water
SLC
SOLUTE CARRIER PROTEIND (UPTAKE AND EFFLUX)
ABC
ATP BINDING CASSETTE PROTEINS(efflux)
slc FAMILY

OAT [ORGANIC ANION TRANSPORTER]

OATP [ORGANIC ANION TRANSPORTER PROTEIN]

OCT[ORGANIC CATION TRANSPORTERS]

MATE [MULTIDRUG AND TOXIN EXTRUSION] 

OATP FOUND WHERE

ON APICAL SIDE OF ENTEROCYTE

 

[INHIBITOR: GRAPEFRUIT,Ornge juice]

 

[SUBSTRATE: FEXOFENADINE]

OAT1 [FOUND WHERE]

IN KIDNEY TUBULES

 

UPTAKE OF GLYCINE CONJUGATES FROM BLOOD INTO KIDNEY

 

WHAT DRUG INHIBITS OAT1

PROBENECID

 

 

[OAT1 Substrate: P-aminohippurate]

OCT (ORGANIC CATION TRANSPORTER)[WHERE FIND]

TAKES UP DRUG FROM BLOOD INTO HEPATOCYTE(LIVER)

 

[Substrate: METFORMIN]

 

[Inhibitor: Cimetidine]

 

MATE [FIND WHERE]

 

 

LIVER AND KIDNEY

 

TAKES CATIONS OUT[EFFLUX]

SLC

 

[from hepatocyte to bile, kidney to urine]

 

ex:metformin

MATE INHIBITOR

CIMETIDINE

 

[also an OCT inhibitor]

ABC REQUIRE________
ATP
MATE DISCOVERED FIRST IN

CANCER CELLS

[TOO MUCH EFFLUX PROTEIN CAUSES MULTI DRUG RESISTANCE] 

MDR1 (MULTI DRUG RESISTANCE PROTEIN 1)

AKA p glycoprotein[usually passive lipophilic dif]

 

EFFLUX PROTEIN 

(IN INTESTINE)

 

LIMITS DRUG ABSORPTION IN ENTEROCYTES

MDR1 RECOGNIZES______ AND _____ DRUGS

NEUTRAL AND WEAKLY CATIONIC

 

[SUBSTRATES ARE BULKY]

MDR1 SUBSTRATES 

(BULKY ISH)

LABETOLOL

LOPERAMIDE

 

MDR1 INHIBITOR

VERAPAMIL

 

[USUALLY USED AS A TEST TO SEE WHATOTHER DRUGS BIN P GLYCOPROTEIN]

ANION EFFLUX PROTEINS (2)

MRP2 =MULTI DRUG RESISTANT PROTEIN 2

BCRP= BREAST CANCER RESISTANT PROTEIN

mrp2 (MULTI-DRUG RESISTANCE PROTEIN 2)

 

(FOUND WHERE)

LIVER, BRAIN, INTESTINE,KIDNEY (*bilk mneumonic)

 

 

mrp2 (MULTI-DRUG RESISTANCE PROTEIN 2)

 

SUBSTRATES<<

INDINAVIR

CISPLATIN

ACETAMINOPHEN GLUCURONIDE

bcrp (BREAST CANCER RESISTANCE PROTEIN)

 

FOUIND WHERE????(*PILB mnuemonic)

PLACENTA

INTESTINE

LIVER 

BREAST

bcrp (BREAST CANCER RESISTANCE PROTEIN)

SUBSTRATES……

 

 

 

 

 

effluxed several cancer drugs(first found in mdr breast cancer cells)

estrone sulfate

 

methotrexate

ABC FAMILY ?

MDR1

MRP2

BCRP

SLC FAMILY?

OAT

OATP

OCT

MATE(EFFLUX)

LIPID SOLUBLE DRUGS(5)

JANITOR    (*mops p  MNEUMONIC)

 

Morphine

Ondansetron

Prednisone

Simvastatin

Pentobarbital (most of barbiturates)

UPTAKE transporters (*OOO mnuemonic)

OAT1
OATP 

OCT

Paracellular drugs (water soluble)

 (MAA*)

Metfromin

Acetaminophen

Aspirin

Efflux Transporters(MMMB*)

MATE

MDR1

MRP2

BCRP

x

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