1. INTERPATIENT VARIABILITY OF DRUG DISPOSITION & DOSAGE ADJUSTMENT
Readings (Applied Biopharm & PK 5th Ed.):
Chp 12. Pharmacogenetics p
Chp 21. Renal & Hepatic Disease p
Chp 20. Peds/Geriatrics/Obesity p
Several articles will be posted on-line.

2. Objectives Identify variation in response
Understand underlying genetic, environmental and pathophysiological factors responsible for patient differences in drug response.
Evaluate clinical significance
Individualize drug therapy based on specific patient factors (using knowledge, logic and available equations).
“Personalized Medicine”

3. One Size (or Dose) Fits All
20th Century Medicine:
One Size
(or Dose)
Fits All
Currently use “trial and error” method of prescribing

4. IS IT EFFECTIVE? Drugs Non-responders TNFa inhibitors >40%
Medicine’s Dirty Little Secret-
only 50% of patients respond to major drug groups.
Drugs Non-responders
TNFa inhibitors >40%
Tricyclic antidepressants %
SSRI antidepressants %
Beta-blockers %
ACE inhibitors %
5-HT1 blockers (migraine) %
HMG CoA red. inhibitors %
Interferons %
Anti-neoplastics %

5. IS IT SAFE?
Adverse drug reactions (ADRs) represent the 4th leading cause of hospitalization and is responsible for 100,000 deaths/yr in the U.S.
U.S. Health Management Organization (HMO) data suggest that the healthcare cost of treating drug ADRs exceeds the cost of providing the medications themselves
2 million hospitalizations/yr in US
Cost estimates range between billion/ yr in US.

6. Interpatient variability of drug response
Inter-patient variability in response to drug therapy is the rule, not the exception for almost all medications.
Research in the past years has identified many sources of inter-patient variability- which can be used for drug and dosage selection.
New knowledge, particularly in the area of pharmacogenetics, is progressing at a rapid pace.

7. Variation in drug response Why?
Environment
&
Physiology
Genetics
Absorption
Distribution
Metabolism
Excretion
Target Interaction
Drug
Response
Drug

8. Warfarin
From Brian Gage;
Other relevant slides:

9. Factors which impact warfarin dose requirements
Environmental
Age
Gender
Drugs
Body wt
Race
Diet
Others
UNKNOWN
CYP2C9
VKORC1
Genetic
<Caldwell M., CPSC Advisory Committee Meeting, November 14, 2005>

10. ENVIRONMENTAL & PHYSIOLOGICAL
FACTORS
- Exposure to drugs / toxins/ pollutants
- Diet
- Disease
- Age
- Weight
- Gender/ hormones
- Exercise
- Others?
Lets look at several important examples of environmental factors which impact the absorption / distribution / elimination of drugs.
Multiple factors can play a role.

11. A. Absorption Influenced by: Permeability
Motility
Active Transporters
Metabolic Enzymes
1. May be altered in diseases of GIT
Colitis- diarrhea, flu
 motility;  absorption
Inflammation (Crohn’s, IBD)
scar tissue:  absorption
Cystic fibrosis
Mucus & electrolyte changes,
Malabsorption
Malnourishment
 F of Vitamin & minerals
Achlorhydria
 pH -Dose dumping of Enteric coated

12. uptake transporters :  oatp
2. May be altered by diet.
Grapefruit juice
 CYP3A4 & PGP in gut
 (up to 3X) drug concentrations: cyclosporin A (CsA) , terfenadine,
midazolam, felodipine, Ca++ channel
blockers, talinolol
uptake transporters :  oatp
Altered bioavailability of substrates such as fexofenadine, digoxin, pravastatin, atorvastatin

13. Example Effect of Grapefruit juice (300 ml- taken with drug) on bioavailability of fexofenadine.
GFJ decreases intestinal expression of OATP- an active transporter involved in the uptake (absorption) of fexofenadine.
Bioavailability reduced by half.

14. 3) May be altered by drugs or natural products
Herbal products
Induction of intestinal CYP3A and PGP by St John's Wort.
Decreased oral availability of drug substrates. (CsA, indinavir, digoxin)
Cyclosporin- has resulted in numerous cases of organ transplant rejection.
Decreased effectiveness of oral contraceptives.
-Potential for unplanned pregnancy

15. B. Distribution Changes in body composition
1) Disease-associated changes in plasma protein concentrations.
albumin:  binding:  Vd
- NSAIDs
 α1-acid glycoprotein:  binding,  Vd
-propafenone, propranolol
2) Obesity
 distribution of fat soluble drugs
3) Pregnancy
 fat,  water,  weight, placenta
Age
Changes in body composition
5) Altered blood-brain barrier
Disease-induced changes in expression of drug transporters at BBB
Altered permeability of membrane
* Will cover in more detail in future lectures

16. C. Elimination 1) Environmental Toxins 2) Food 3) Drugs 4) Disease
There are numerous examples where hepatic and renal elimination is affected by environmental or physiological changes.
1) Environmental Toxins
2) Food
3) Drugs
4) Disease
5) Age
6) Pregnancy

17. Environmental Pollutants: Polycyclic Hydrocarbons induce P450s
Smoking
Charcoal Broiling
Pollutants
Increased drug clearance:
theophylline, phenacetin
Food:
High protein diet:  creatinine
Alcohol:  P450
Red Wine:  Cyclosporin A levels

18. Some known CYP P450 Inducers:
DRUGS
flockhart/table.htm
A. Induction of Metabolism
Some known CYP P450 Inducers:
CYP 1A2
cigarette smoke, omeprazole,
phenobarbitone
CYP2D6
dexamethasone, rifampin
CYP2E1
Ethanol, isoniazid
CYP3A
Barbiturates, carbamazepine, ethosuximide,
glucocorticoids, phenobarbital, phenytoin, rifampicin, …..

19. Some known CYP P450 Inhibitors:
DRUGS
B. Inhibition of Metabolism
Some known CYP P450 Inhibitors:
CYP 1A2
- cimetidine, fluoroquinolones
CYP2D6
- fluoxetine, quinidine, paroxetine
CYP2E1
- cimetidine, disulfiram
CYP3A
- eg. HIV protease inhibitors, antimicrobials (clarithromycin, erthryomycin, ketoconazole)
- many more

20. C. Inhibition of Hepato-Biliary Secretion
DRUGS
C. Inhibition of Hepato-Biliary Secretion
P-glycoprotein (efflux transporter)
Quinidine/ quinine + digoxin:
-  CLbile digoxin (50-60%)
Oatp (influx transporter)
Gemfibrozil + statins:
- 2X ↑ AUC pravastatin (ed hepatic uptake)
- 4 X ↑ AUC cerivastatin
Cyclosporin A + statins:
- 4X ↑ AUC cerivastatin
- 7 X ↑ AUC rosuvastatin (ed hepatic uptake)

21. D. Inhibition of Renal Secretion
DRUGS
D. Inhibition of Renal Secretion
P-glycoprotein (efflux transporter)
Quinidine + digoxin:
-  CLr digoxin (50-60%)
Ritonavir + digoxin:
- CLr digoxin
Oatp (influx transporter)
Probenecid + Cephalosporins:
- CLr
- 1.8X CLr with 2.4 X ↑ AUC cephradine
OCT (organic cation transporter)
Cimetidine :
- CLr procainamide from 347 to 196 ml/min
(↑AUC procainamide)
- CLr metformin from 527 to 378 ml/min

22. Diseases
Drug metabolism and secretion is decreased in a variety of diseases which are associated with an inflammatory response.
infection, arthritis, Crohn’s disease, renal disease, cancer etc..
Altered drug PK and drug response is seen both clinically and in experimental animal disease models.

23. Cancer
Inflammatory response induced by tumor growth has been shown to decrease activity of drug metabolizing enzymes in Cancer patients.
(14C- Erythromycin Breath test) in Cancer Patients
CYP 3A
Enzyme
Activity
Levels of Inflammation Marker
(C-reactive Protein)

24. Arthritis
CYP P450 Activity
 Protein binding

25. Increased Fetal Accumulation Increased Maternal Accumulation
Bacterial Infection
- Altered disposition of P-Glycoprotein Substrate (99Tc-Sestamibi) in Pregnant Rats
Increased Fetal Accumulation *
Increased Maternal Accumulation
-Infection
Brain
Liver
Kidney
Intestine
Placenta
Altered Maternal and Fetal Disposition- due to decreased expression and activity of P-glycoprotein

26. Advanced kidney disease can impact the
Renal Disease
Advanced kidney disease can impact the
metabolism, intestinal and/or hepatobiliary elimination of non-renally cleared drugs
1)  Pgp and CYP3A in intestine: ↑ oral
bioavailability of Pgp/CYP3A substrates.
- erythromycin, propranolol, tacrolimus
2)  CYP3A & CYP2C11 in Liver:  hepatic
metabolism of substrates.
3)  Hepatic expression of Oatp uptake transporter:  hepatobiliary CL?

27. Ex. Repaglinide in Renal Disease - non-renally cleared oral hypoglycemic (<8% Clr) - Excreted via bile: - extensively metabolized (glucuronidation, CYP3A, CYP2C8) - active transport via Oatp1B1 and ABCB1
Mild/mod disease
Severe disease
Increased AUC due to decreased hepatobiliary clearance: OATP & CYP3A