St. John’s Wort: natural health product
Kanamycin and glucose are P molecules
Lithium treats bipolar disorder
Preclinical testing: in cultured cells, experimental animals. Evaluate biological effects,
pharmacokinetics, toxicity
Clinical trial application: submitted to Health Canada prior to human studies
Phase I clinical trial: 20-100 healthy volunteers. Evaluation of pharmacokinetics and
pharmacodynamics
Phase II clinical trial: 300-500 patients w/disorder. Therapeutic effectiveness, side effects and
dosing information
Phase III clinical trial: 500-5000patients w/disorder. Therapeutic effectiveness, long term side
effects
New Drug Submission (NDS) submitted to Health Canada; details therapeutic effectiveness &
safety. If approved, health Canada issues a Notice of Compliance (NOC) and a Drug Information
Number (DIN) to market drug
Phase IV clinical trial: post marketing surveillance; monitor efficacy and safety of drug
Oral drug → stomach → small intestine → portal vein → liver (metabolism) → systemic circulation
→ tissues
Liver → gall bladder via bile duct → large intestine → fecal excretion (secondary)
Parenteral injection; absorbed from injection site into systemic circulation, bypasses liver.
Tight jxns prevent molecules b/w cells
SER metabolizes drugs, carbohydrates and steroids. RER synthesizes p-
Small compounds <200 through channels/pores (selective). Ions mostly, not every small ion can
pass through a channel, depends on charge
Specific transport p- move drugs.
Uptake transporters: intestinal absorption, renal excretion and reaching target action site inside
cell
Efflux transporters: intestine, placenta, kidney and at BBB
Aspirin: weak acid. Amphetamine: weak base
Nitroglycerine for angina sublingually
Albumin: for lipophilic acidic drug. Alpha 1 acid glycoprotein: for hydrophilic basic drug
Ethanol: example of zero order kinetics metabolism
CYP: (12) families of drug metabolizing phase 1 enzymes, oxidize drugs. Malnutrition ↓ CYP
activity
CYP3A4 metabolizes 50% of currently marketed drugs
Liver, kidney diseases, inflammation and infection decrease CYP activity
Phase 2 metabolic enzymes (fraction of drugs metabolized split evenly among UGTs, SULTs,
GSTs, NATs)
1. UDP-glucoronosyltansferases (UGTs): in SER. Catalyze transfer of a glucuronic acid
(sugar) to a drug, making it more P, easily excreted. 19 UGT enzymes 2. Sulfotransferases (SULTs): cytosol, catalyze transfer of a sulfate group to a hydroxyl
group of drug, more P. 11 SULT enzymes
3. Glutathione S Transferases (GSTs): cytosolic or microsomal, catalyze transfer of a
glutathione molecule to a reactive/toxic drug → less toxic. 20 GST enzymes
a. Glutathione(GSH) is an intracellular antioxidant
4. N-acetyltransferases (NATs): cytosol, catalyze transfer of an acetyl group from acetyl
CoA to a drug, making it more water soluble. 2 NAT enzymes (1 & 2)
a. Subject to genetic polymorphisms → drug response variability.
5. Thionpurine Metytransferase (TPMT): cytosolic, catalyze transfer of a methyl group
from S-adenosylmethionine to a drug
a. Subject to genetic polymorphisms (variability), has effect on drug safety
Phase 1 SNPs:
CYP2C9: metabolizes the anticoagulant drug warfarin. SNP results in decreased enzyme
activity, therefore, patients with SNP in CYP2C9 require lower dose of warfarin
CYP2D6: metabolizes codeine to morphine (more potent). Has many genetic SNPs that can
result in 4 phenotypes
1) Ultra-rapid metabolizer: significantly increased CYP2D6 activity; more morphine, good pain
relief but side effects of morphine. Possess multiple copies of the CYP2D6 gene
2) Extensive metabolizer: normal enzymatic activity
3) Intermediate metabolizer: reduced metabolic activity
4) Poor metabolizers: have no metabolic activity, inadequate pain relief
Phase 2 SNPs:
UGT1A1: glucuronidates the anti-cancer compound SN-38 (the active metabolite of irinotecan).
SNPs in UGT1A1 decrease its activity. Increased diarrhea and bone marrow suppression (side
effects from drug)
NAT2: acetylates the drug isoniazid (treats TB), caffeine and cancer causing chemicals.
23 different SNPs in NAT2 gene. Patients classified as rapid or slow acetylators based on
genotype
Slow acetylators more susceptible to isoniazid toxicity, higher risk for cancer
Dopamine: agonist drug causes different effects depending on the dose.
Low dose to dopamine receptor: renal artery vasodilation, increased renal BF, increased urinary
output
Moderate dose to B1 adrenergic receptor: increased CO
High dose to alpha adrenergic receptor: renal artery vasoconstriction, decreased renal BF,
decreased urinary output
Antagonists
Beta blockers: block binding of endogenous E to beta 1 receptors in the heart, slows HR
Anti-histamine: block binding of histamine to H1 histamine receptors in the nasal mucosa,
prevents allergy symptoms
Gastric acid reducers: block binding of histamine to H2 histamine receptors in the gut,
decrease gastric acid secretion into stomach
Opioid receptor blockers: block binding of opioids to opiate receptors, used in treating opiate
overdose Rosuvastatin: higher [] in Asians, therefore need lower dose
Smoking induces drug metabolizing enzymes
Antihistamines block H1 histamine receptor to prevent vasodilation (runny nose, watery eyes),
therefore get vasoconstriction (no allergy symptoms). Side effects b/c antihistamines bind in
brain (drowsiness, dry mouth and urinary retention).
Allergic rxns: penicillins, sulfonamindes, nonsteroidal anti-inflammatory drugs (NSAID)
Blood test determines if person is at risk for idiosyncratic rxn due to genetic polymorphisms for
the drugs warfarin (blood thinner metabolized by CYP2C9) and 6-mercaptopurine
(metabolized by thiopurine methyltransferase TPMT)
Examples of genetic polymorphisms that cause idiosyncratic rxns:
• CYP2C9: approx. 15% Caucasians have a polymorphism that decreases metabolism
• CYP2D6: 10% Caucasian and African American are poor metabolizers therefore don’t
experience pain relief with codeine (a pro-drug metabolized by CYP2D6 to morphine)
• Thiopurine methyltransferase (TPMT): 10% patients have decreased activity, 0.3%
have no activity. Treatment with thiopurine drugs in patients with low or absent TPMT →
life threatening bone marrow suppression
• OATP1B1 (uptake drug transporter in the liver; drugs from blood into liver). 15% Asian
and Caucasian patients have a polymorphism that decreases fxn. ∴ increase in plasma
drug concentration. This polymorphism causes myopathy (muscle toxicity) in patients
taking statin drugs.
• Glucose 6-phosphate dehydrogenase deficiency (G6
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