Barriers: Metabolism Flashcards
Sites of drug metabolism
-first pass: GI epithelium and liver
-systemic: in organs and blood stream
Classes of Metabolism
3 phases
Phase 1 of metabolism
of main compound
-ex: decarboxylases, oxygenase, deamidation
Phase 2 of metabolism
through addition, conjugation
ex: glucuronisation, sulfation
Phase 3 of metabolism
transport-multidrug resistance
Metabolism goals
-eliminate activity of drug
-make a compound more soluble until it cannot escape excretion
How to achieve Metabolism
-change shape to block binding to receptors
-change lipophilic character to hydrophilic for increased solubility
-increase molecule size to be cleared by bile or urine
-make more recognizable by efflux pumps
very lipophilic
-normally reside in fatty tissues
Phase 1 CYP (oxidation, reduction) enzymes
2D, 2C, 3A, 1A, 2B
Phase 2 conjugation enzymes
-SULT
-methyl transferase
-UGT
-NAT
PHase 3: Transporter (ABC, SLC) enzymes
-P-gp
-OATP1B1
Metabolism of tamoxifen SLIDE 42
TAM –(CYP3A4)–> NDM –(CYP2D6)–>4OH-NDM aka Endoxifen, active metabolite
PRODRUG
CYPs
-17 CYPs in humans
-grouped into families with around 40% amino acid homology
-70 mammalian CYPs
Cytochrome P450 family
-CYP3A4 major focus of phase 1 metabolism
-though CYP3A5 might metabolize what we though CYP3A4 did (similar isoforms)
Drug-Drug interactions
can alter drug elimination
-xenobiotics like grapefruit and orange juice
Nonlinear PK
leads to nonlinear TK
Rectum epithelia
-simple columnar (upper half)
-stratified squamous non-keratonized region transitions to strat squamous keratinized region (lower half near anal sphincter)
Absorption by surface area
- stomach
- jejunum
- cecum (way lower)
Role of stomach
-digest food and control its flow
-food reservoir
-food to fluid chyme for absorption
-pH protects against most bacteria, allows pepsin to function
Stomach
-fasting pH < 3
-fed pH 5 to 7
-30 min emptying half
-fasting state: 4 phases of emptying ending with Housekeeper wave
-fed state, no defined cycle
Stomach organization
-fundus
-body
-antrum
fundus of stomach
-upper
-contains gas
-produces contractions to move food
Body of stomach
-middle
-reservoir for food/fluids
Antrum of stomach
-lowest
-funnel shaped
-pyloric region
-controls flow to small intestine
Emptying cycle
-cycle of 4 phases
-eating stops the progression of the cycles
-starts over when stomach empties
Phase 1
-40-60 min no activity
Phase 2
-mixing contractions in stomach and small intestine
-40-60 min
Phase 3
-powerful contractions empty stomach
-peristalsis by small intestine
Phase 4
-contractions diminish
-stomach empty
Cold carbonated drinks
-rapidly induce emptying
big-mac
-basically halt gastric motility
The intestine
-3 hour transit time
-site of most absorption
-pH=5-6.5
colon drug absorption
occurs in ascending region nearest to small instestine
Small Intestine
-site of most absorption
-house most transporters
-5-6m long
colon
fluid and electrolyte absorption
small intestine regions
- duodenum
- jejunum
- Ileum
small intestine compostition
serosa, muscles, submucosa, mucosa
-villi and crypts
upper small intestine
mixing
lower small intestine
electrolyte absorption
Intestinal absorbing surface area
-increases due to folding
cylinder< folds < villi < microvilli
Columnar epithelial cells
-form single continuous layer of absorptive cells covering each villus
-separated from lamina propia by basal lamina
-crypt region and villus region
-crypt cells, goblet cells, M cells
basal lamina
-separates columnar epithelium from lamina propia
-comprised of glycoproteins
-penetrable by lymphocytes
lamina propia
blood vessle and lymph
crypt region
-3x more crypt than villi
-undifferentiated cells that proliferate
-Goblet, Paneth, Argentaffin cells
goblet cells
-crypt region
-some in villus region
-mucus secreting
paneth cells
-regulate microflora
-crypt region
Argentaffin cells
-secrete mucos component
-crypt region
Villus region
-absorptive enterocytes
-few goblet cells
-M cells overlay the peyer’s patch or lymphoidal tissue
GI tract turnover
-every 2-4 days
-cells from crypt migrate up to villus tip and then sloughed off
-enterocyte life span 2-3 days
Intestinal muscle
-can affect integrity and absoprtion
-contractility changes by IBS, crohn’s, etc alter transit time and absorption
Colon
-slower transport
-varies in thickness from sigmoid to caecum region
-water and electolyte absorption
-promote solid stool
-ileocaecal valve
-ascending, transverse, descending
Ileocaecal valve
-limits blood flow from ileum into caecum and vice versa
Colon structure
-serosa
-muscularis externa
-submucosa and mucosa
serosa
squamous epithelium covered with adipose tissue
muscularis externa
-inner circular muscle layer and incomplete outer longitudinal layer
Colonic Mucosa layers
-muscularis mucosae
-lamina propia
-epithelium
Proximal colon
usually where eneteric coated formulations target by oral administration
Distal colon-rectal administration
-suppositories
-some young and old patients with gag reflexes
-low residence time
-high absorption
Gastrointestinal rates
SLIDE 81
-slowest in elderly people
Relationship between stomach emptying and colonic retention
As stomach empties, colon absorbs
Rectum
-upper and lower half
-highly folded
-high absorption
-low residence time
-route of administration
Upper rectum
simple columnar
Lower rectum
-stratified squamous, non-keratinized region near anal sphincter
-this epithelium allows high drug absorption
Variabilities in drug response
-genetic factors (drug targets, transporters, enzymes)
-environmental factors (induction and inhibition)
-physiological factors (age, disease)
Considerations for Oral Absorption
-Disintegration/ Deaggregation of particle
-Dissolution to crystalline or amorphous form
-Free API to intestinal flora, bile, nucleate, absorption
Potential barriers of drug absorption
-food
-pH
-protein binding
Biorelevant Dissolution Times
-effects of formulation and food on dissoulution and availability of orally administered drugs
Mean residence time
average time drug stays in body
Stomach volume
lower when fasting
small intestine volume
higher when fasting
large intestine volume
lower when fasting
GI transit time variation
-residence differs
-emptying controls colonic retention
-more residence = more absorption
-pH and residence changes occur even when drug taken before meals
GI luminal fluids
-jejunum
-ileum
-colon
jejunum fluids
-lowest pH of the luminal fluids (7.08-7.6)
-lowest buffer capacity (3.23-4.5)
-ONLY one with bile salt content (2.88-4.6)
Factors influencing solubility
-buffer capacity
-bile salts
-regional fluids
-other drugs
-endogenous substrates
Variables along the GI tract
-transporters and enzymes
-fluid composition
-diet and chemical exposure
-pharmacogenetics and genomics
-interindividual variation
-drug-nutrient and drug-drug interactions
