Biotransformation Flashcards
1
Q
Biotransformation
A
- chemical modification made by organisms on a chemical compound
- make non-polar compounds polar ⇒ can be excreted rather than reabsorbed
- intermediary metabolism
2
Q
Drug metabolism
A
- xenobiotic metabolism
- often converts lipophilic compounds into more hydrophilic
- rate of metabolism determines the duration and intensity of a drug’s pharmacological action
3
Q
Phase 1 metabolism
A
- may occur by oxidation, reduction, hydrolysis, cyclization, decyclization etc
- often in liver
- oxidative reactions involve cytochrome P450 monooxygenase, NADPH and oxygen
- purpose is to make compound more water soluble
4
Q
CYP1
A
- CYP1A1, CYP1A2, CYP1B1
- inducers: methylcholantrene, dioxin derivatives, environmental pollution, cigarette smoke ⇒ bronchial carcinoma
- substrates: polycyclic aromatic hydrocarbons PAH, medicines(teophyllin, caffeine, phenacentine)
5
Q
CYP-2
A
- inducers: phenobarbital, ethanol, acetone, diazepam derivatives
- CYP2A ⇒ synthesis of steroids and testosterone
- CYP2B ⇒ progesterone, Vitamin D3, antiepileptics
- CYP2C ⇒ mephenytoin-antiepileptics
- CYP2D ⇒ metabolism of antidepressants, beta-blockers, antihypertensives
- CYP2E ⇒ metabolism of ethanol acetone; associated with diabetes mellitus, starvation periods
6
Q
Cytochrome P450 system
A
- RH + O2 + NADPH + H+ ⇒ ROH + H2O + NADP+
- contain heme cofactor (hemoprotein)
- genes mainly expressed in liver, lungs, intestines, skin and kidneys
- drugs absorbed from GI ⇒ portal vein ⇒ liver
7
Q
CYP-3
A
- inducers: steroids- oral contraceptives, PCN
- substrates: antibiotics, nifedipine, cyclosporine
8
Q
CYP-4
A
- inducers: clofibrate
- substrates: fatty acids, eicosanoids
9
Q
Phase 2 metabolism
A
- conjugation
- joining the compound with another molecule such as glucuronic acid
10
Q
Glucuronidation
A
- enzyme catalyzing: UDP glucuronosyl transferase
- transfer of glucuronic acid from UDPGA to substrate that contain oxygen, nitrogen, sulfur or carboxyl functional group.
⇒ more polar glucuronide and more easily excreted than the substrate - UGT’s activate: morphine, bile acids, steroids, retinoids, PAH’s
11
Q
Morphine
A
- 40-50% metabolized in first pass through liver
- 87% excreted in urine within 72h
- metabolized into M3G and M6G via glucuronidation by UGT2B7
- 60%⇒ M3G ⇒ no opoid receptor binding, no analgesic effect
- 6-10%⇒ M6G ⇒ binds to u-receptors
- metabolized in liver, brain, kidney
12
Q
Hyperbilirubinemias
A
- breakdown of heme ⇒ bilirubin ⇒ glucuronidation ⇒ Bilirubin diglucuronide ⇒ excreted by liver in bile
- intestinal bacteria deconjugate ⇒ urobilinogens ⇒ some absorbed and goes to kidneys and urine/ some down digestive tract as stercobilinogen⇒ stercobilin
13
Q
Gilberts syndrome
A
- unconjugated hyperbilirubineamia, hereditary disease
- increased bilirubin
- symptom: jaundice, increased unconjugated bilirubin in blood
- cause: reduced activity of UGT, SNP (point mutation)
- treatment: phenobarbital
14
Q
Crigler-Najjar syndrome
A
- unconjugated hyperbilirubinemia
- cause: early stop codon in UGT genes
- very rare
- symptom: brain damage in infant
15
Q
Conjugated hyperbilirubinemias
A
- Dubin Johnson syndrome
- Rotor syndrome
- caused by problem with transport out of liver via MRP2
- defect in gene of this transporter, build-up of conjugated bilirubin in blood ⇒ jaundice
