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U N I V E R S I T Y O F K E N T U C K Y - C O L L E G E O F P H A R M A C Y
Pharmacokinetics & Drug Transport
Philip E. Empey, Pharm.D., Ph.D., BCPS Assistant Professor, Department of Pharmacy and Therapeutics
805 Salk Hall, School of Pharmacy
University of Pittsburgh
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Pharmacokinetics The study of the time course of a drug in
the body and the biological and chemical processes affecting absorption, distribution, metabolism, and excretion.
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Dru
g co
ncen
trat
ion
in b
lood
Time
TOXIC
No Effect
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Liver
SystemicCirculation
Tissues
Kidney
Met
abol
ism
Dis
trib
utio
n
Abs
orpt
ion
Exc
reti
on
GI
Pharmacokinetics: ADME
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Drug Absorption
http://www.nlm.nih.gov/medlineplus/
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Drug Absorption
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Absorption Transport Processes
Blood
Lumen
ATP
H+
H+ H+
H+H+
H+
H+
H+H+
ATP
Facilitated Active ActivePassive
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Absorption Transport Proteins
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Liver
SystemicCirculation
Tissues
Kidney
Met
abol
ism
Dis
trib
utio
n
Abs
orpt
ion
Exc
reti
on
GI
Pharmacokinetics
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Transport proteins in other organs
Some drugs are transported, some act to inhibit these processes leading to drug interactions! Penicillin/probenecid & quinidine/digoxin
Some physiological conditions or diseases change transporter gene expression
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Breast Physiology
Modified from Breastfeeding (1994) by RA Lawrence
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Transporters in breast barrier cellsTransporters upregulated
during lactation
Transporters expressed in LMECs at a level
similar or greater than other secretory tissues
10*7
Transporters upregulated
during lactation
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US breastfeeding trends
Ryan, et al. 2002Ross Labs (Abbott) Breastfeeding Statistics
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Information for prescription drugs?
All Marketed Drugs
n = 1625
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Research techniques Collect breast milk, measure transporter gene expression. Compare drug concentrations in milk and blood in humans
and animals. Grow breast cells in culture and measure drug transport. Develop models to help predict which drugs accumulate in
breast milk.
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Liver
SystemicCirculation
Tissues
Kidney
Met
abol
ism
Dis
trib
utio
n
Abs
orpt
ion
Exc
reti
on
GI
Pharmacokinetics
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Liver is the site of drug metabolism
P450
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Patients in a coma after heart attack now are having their body temperature lowered as a therapy, also being tested for spinal cord injury and trauma.
Hypothermia and pharmacokinetics
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Impact of interventions - hypothermia
Hypothermic circulatory arrest, NIH Clinical Center, 1955
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Impact of interventions - hypothermia
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Relevance for pharmacotherapy
Anticonvulsants
Phenytoin CYP2C9, CYP2C19
Carbamezipine CYP3A4
Calcium Channel Blockers
Verapamil CYP3A4, P-gp
Diltiazem CYP3A4, P-gp
Amlodipine CYP3A4
Inotropes
Digoxin P-gp
Antimicrobials
Aminoglycosides Renal Excretion
β-lactams Renal Excretion, OATs
Caspofungin OATP1B1
Protease Inhibitors P-gp, ABCG2
Macrolides CYP450s
Fluroquinolones CYP450s, ABCG2
Rifampin CYP3A4
Antiarrythmics
Amiodarone CYP3A4
Procainamide N-acetyltransferase
Lidocaine CYP1A2, CYP3A4
β-blockers
Propranolol CYP2D6
Metoprolol CYP2D6, CYP2C9
Atenolol Renal Excretion
Analgesics/Anxiolytics
Midazolam CYP3A4
Fentanyl CYP3A4, P-gp
Statins
Atorvastatin CYP3A4, OATP1B1
Pravastatin OATP1B1, OATP2B1
Ace Inhibitors/ARBs
Valsartan OATPs, MRP2
Enalapril OATPs, MRP2
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Animal experiments Test the effects of hypothermia on drug
metabolism when given after heart attack
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Concentration-time curves
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Children with brain injuries
Measure drug concentrations in the brain and the blood to see cold temperature effect.