Back to the Future with Toxicological Sciences:

Impact on the Art of Pharmacy

Ho Han KiatBSc (Pharmacy, Hons, NUS),

PhD (Medicinal Chemistry, U. of Washington)

Understanding The Audience

• I like to know more about toxicology• I want to learn more about pursuing a

higher degree overseas• What else is out there beyond pharmacy

as a profession?• I came because I was asked to• I came for the refreshment

Talk outline

• How I ended up doing what I am doing• PhD education system in US• What are toxicological sciences• Relevance of toxicology to pharmacy

practice• Opportunities in toxicology

University of Washington- Medicinal Chemistry

University of Washington Seattle, Washington, USA

How I ended up doing what I am doing?

•Most commonly used drug in the world•Most common cause of acute liver failure

How I ended up doing what I am doing?

N

O

OH

N

O

OSO3H

N

O

O-Glucuronide

O

O

NN

O

OH

SG

N

O

OH

S-Hepatic protein

Sulfation Glucuronidation

Paracetamol

P450oxidation

Glutathione

Conjugation Conjugation

Protein

Glutathione depletion

DetoxificationOxidative

stressLiver injury

Prof Sidney D. Nelson

• Dean, School of Pharmacy, University of Washington

• APha Academy of Student Pharmacists Outstanding Dean of the Year 2007

• ISI List of Most Highly Cited Scientists

Chemical Structure Can Predict Toxicity

SO

CH3

H

OOH

Suprofen (Nephrotoxic)

S

CH3

H

OOH

O

Tiaprofenic acid (Interstitial cystitis)

CH3

H

OOH

OKetoprofen (Non-toxic)

PhD Education System In US

• Admission requirements:– 4-year undergraduate education– GRE– TOEFL– Recommendation letters– Essay of intent

• Typically 5 years• Lab rotations in first year• Coursework for 1-2 years• General/qualifying exams• Final exams- thesis defense

What do I wish I’d known before starting PhD

• With a BSc (Pharmacy), you can pursue a PhD in ANY field in biomedical sciences!

• The name of the department tells you nothing about the work they engage in

• Don’t have to wait till you complete your undergraduate to start applying

• A masters is helpful but not necessary• Scholarships are available, you just need to

know where to find them

What is Toxicology?

“Poison is in everything, and nothing is without poison. The dosage makes it either a poison or a remedy.” Paracelsus (1493-1541)

“It is impossible to differentiate between therapeutic herbs and poisons” Da Chang Jin (around 1494-1544)

Approximate LD50 Of Some Chemical Agents

Agent LD50 (mg/kg)Ethyl alcohol 10000Sodium chloride 4000Ferrous sulphate 1500Morphine sulphate 900Phenobarbital sodium 150Picrotoxin 5Strychnine sulphate 2Nicotine 1D-Tubocurarine 0.5Hemicholinium 0.2Tetrodotoxin 0.1Dioxin (TCDD) 0.001Botulinum toxin 0.00001

Casarett & Doull’s Essentials of Toxicology, 2003

Drug?

Poison?

Definitions• Toxicology is the science that deals with the study of

adverse effects (toxicities) of chemical, biological or physical agents that may produce in living organisms under specific conditions.

• Who: Who is at risk? • What: Direct? Idiosyncratic?• Where: Which organ is targeted?• When: Immediate or delayed?• Why: Oxidative stress, binding to macromolecules?• How: What molecular mechanism(s) are invoked?

Toxicology: An Integral Part Of Drug Development

Reasons for failure in clinical development. (Data for 198 development compounds*)Reasons for failure PercentagePharmacokinetics 39Lack of efficacy 30ToxicologyToxicology 1111Adverse effects in manAdverse effects in man 1010Commercial considerations 5Others 5Note: Of 198 compounds, 77 were anti-infective drugs; if these are excluded, lack of efficacy was the main cause (49%) and PK failures were less common (7%). * Kennedy T, Drug Discovery Today 1997, 2, 436-444.

Why Should We Care About Toxicology?

Iatrogenic causes are the 3rd leading cause of death

Iatrogenic Causes No. of deaths per year

Unnecessary surgeries 12,000

Medication errors 7,000

Other errors in hospital 20,000

Nosocomial infections 80,000

Adverse drug reactions 106,000Total 225,000

Cost of ADR: 136 Billion USD annually!!!

Drug Toxicity- The Major Cause For Drug Withdrawal

Drug Toxicity- The Major Cause For Drug Withdrawal

Drug Toxicity- The Major Cause For Drug Withdrawal

Notable Withdrawal From Market In The Last 10 Years

• Fenfluramine (1997)- Cardiotoxicity• Mibefradil (1998)- Dangerous interaction• Bromfenac (1998)- Hepatotoxicity• Terfenadine (1998)- Cardiac arrythmias• Cisapride (2000)- Cardiac arrythmias• Troglitazone (2001)- Hepatotoxicity• Cerivastatin (2001)- Rhabdomyolysis• Rofecoxib (2004)- Myocardial infarction• Valdecoxib (2005)- Myocardial infarction• Pemoline (2005)- Hepatotoxicity• Tageserod (2007)- Myocardial infarction

Toxicology Whose job is it anyway?

Not me! I can’t diagnose

I don’t make drugs.I know no chemistry

I just synthesize

what I was told

It better not haveanything to do

with me

The Multi-disciplinary Nature Of Toxicological Sciences

Toxicology

Biology Pathology

Pharmacology

Physiology

Molecular biology

Immunology

Chemistry

Epidemiology

Statistics

Genetics

How is Toxicology Relevant to Pharmacists and Pharmacy Practice?

• Broad-based education in medical, pharmaceutical, biological and chemical sciences allows us to appreciate toxicology

• As the “master of drugs”, we have the moral and professional responsibility to advocate the safe use of drugs

• We are to educate other healthcare professionals about drug toxicities

The Use Of Toxicological Knowledge- 3 Examples

• Restore public confidence on previously failed drugs. E.g. Thalidomide

• Clarify misintepretation. E.g.Sulphur drugs• Dispense the right information about non-

pharmaceutical toxicities. E.g. TEFLON

Thalidomide

• Introduced in 1956 as a mild sedative and against morning sickness

• Severe teratogenic effects with malformation of limbs• Withdrawn in 1961• US FDA issued the first guidelines for reproductive

toxicology testing in preclinical drug development

Thalidomide- Mechanism Of Toxicity

Intercalate DNAGuanine-rich region

Thalidomide- Stereochemistry Affecting Toxicity

GC-rich regions of DNAParticularly promoters of FGF2 and IGF1

Google image

Thalidomide- Mechanism of Toxicity

• Promoters of genes encoding integrin subunits and growth factors: IGF-1 and FGF-2 are guanine-rich

• Highly abundant in cells involved in limb bud development and angiogenesis

Stephens TD, 2000

Sulfa drugs- Hypersensitivity

Stevens Johnson Syndrome

Are Sulphur Drugs-induced Hypersensitivities Due To Sulphur?

NH2 SO

ONH

ONNH2 S

O

ONH

O

Sulfamethoxazole Sulfacetamide

NH2 SO

ONH2

Dapsone

NN

SO

ONH2

CF3

Celecoxib

No hypersensitivity

Haptenization of Sulfamethoxazole

NH2 SO

ONH

ONNH

SO

ONH

ONOH

N SO

ONH

ONO

SulfamethoxazoleProtein binding

(Hapten formation)

Hypersensitivityreaction

Toxicology: An Environmental Issue

TEFLON coating: A polymer of tetrafluoroethylene

Metabolism of TFEC

Job Opportunities

• Industrial/pharmaceutical toxicologists• Clinical toxicologists• Forensic toxicologists• Ecotoxicologists• Regulatory toxicologists

Industrial/pharmaceutical Toxicologists

• Safety testing of new products• Check for contamination of industrial

processes• Work opportunities:

– Pharmaceuticals– Petrochemicals– Cosmetics– Food and beverages– Medical diagnostics

Clinical Toxicologists

• Clinical assessment of adverse drug reactions

• Treatment of poisoning events• Work opportunities:

– Hospitals– Universities

Forensic Toxicologists

• Establish and explain circumstances of legal cases where drugs and chemicals are implicated

• Analytical testing of biological samples• Work opportunties:

– Forensic departments

Ecotoxicologists

• Study the toxic effects of chemicals on the environment and populations

• Tracing movement of pollutants through the ecosystem

• Work opportunities:– Environment and public health agencies– Water treatment plants

Regulatory Toxicologists

• Assessment of toxicological data- do they satisfy legal requirements for licensing

• Work opportunities:– Government agencies

Conclusion

Back to the Future with Toxicological Sciences: Impact on the Art of Pharmacy

Closing Words

“You too, can be a toxicologist in two easy lessons, each of ten years”

Prof Arnold Lehman (1900-1979)