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

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.

Dru

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TOXIC

No Effect

Liver

SystemicCirculation

Tissues

Kidney

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Pharmacokinetics: ADME

Drug Absorption

http://www.nlm.nih.gov/medlineplus/

Drug Absorption

Absorption Transport Processes

Blood

Lumen

ATP

H+

H+ H+

H+H+

H+

H+

H+H+

ATP

Facilitated Active ActivePassive

Absorption Transport Proteins

Liver

SystemicCirculation

Tissues

Kidney

Met

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Dis

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Abs

orpt

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Exc

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GI

Pharmacokinetics

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

Breast Physiology

Modified from Breastfeeding (1994) by RA Lawrence

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

US breastfeeding trends

Ryan, et al. 2002Ross Labs (Abbott) Breastfeeding Statistics

Information for prescription drugs?

All Marketed Drugs

n = 1625

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.

Liver

SystemicCirculation

Tissues

Kidney

Met

abol

ism

Dis

trib

utio

n

Abs

orpt

ion

Exc

reti

on

GI

Pharmacokinetics

Liver is the site of drug metabolism

P450

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

Impact of interventions - hypothermia

Hypothermic circulatory arrest, NIH Clinical Center, 1955

Impact of interventions - hypothermia

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

Animal experiments Test the effects of hypothermia on drug

metabolism when given after heart attack

Concentration-time curves

Children with brain injuries

Measure drug concentrations in the brain and the blood to see cold temperature effect.