Download Understanding the Gastrointestinal, Drug and Dosage Form

Understanding the Gastrointestinal,
Drug and Dosage Form Processes
Controlling Absorption I. GI Physiology
Steven (Steev) C Sutton BS Pharmacy, PhD
Associate professor and Chair
Department of Pharmaceutical Sciences
College of Pharmacy
University of New England
July 25, 2013
AAPS Webinar: I. GI Physiology
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Understanding the Gastrointestinal,
Drug and Dosage Form Processes
Controlling Absorption
I. GI Physiology
II. Biopharmaceutics of oral drug
absorption.
III. Preclinical Models and Simulation
Tools: Successful Integration and
Optimized Clinical Outcome.
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AAPS Webinar: I. GI Physiology
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http://www.globeimages.net/data/media/5/portland_headlight.jpg
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Acknowledgements
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Learning Objectives
• Describe the anatomy &
physiology of the stomach,
duodenum, jejunum, ileum, ilealcecal junction, and the
ascending, transverse and
descending large intestine.
• Describe what when & where the
gall bladder and pancreas secrete
in the small intestine.
• Describe what conditions lead to
a high stomach pH, and what
problems could then arise.
July 25, 2013
AAPS Webinar: I. GI Physiology
http://en.wikipedia.org/wiki/Stomach
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Esophogeal transit


Normal esophageal transit time: 5-15 seconds.
Elderly:
◦ Lack of coordinated tongue, oropharynx, esophagus
movements
◦ Capsule separates from bolus of water
◦ Dry swallow
◦ Capsule sticks;
Perkins, A.C., C.G. Wilson, P.E. Blackshaw, R.M. Vincent, R.J. Dansereau, K.D. Juhlin, P.J. Bekker, and R.C. Spiller, Impaired oesophageal transit of capsule versus tablet formulations in the elderly.
Gut, 1994. 35(10): p. 1363-7.
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Right-hand side:
Rapid gastric emptying
The Gastro-intestinal tract
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Stomach-anatomy
resting volume: 30 ml
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Motility of the stomach
0-2 hrs:
Pylorus is initially
completely shut.
2-4 hrs:
Pylorus allows
2mm particles to
empty
Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Stomach-function
• Acidic pH, enzymes
• Mixing, grinding
• Reservoir (controlled
emptying).
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AAPS Webinar: I. GI Physiology
Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Effect of stomach contractions on
tablet erosion
• grinding forces can disintegrate the
formulations and cause dose dumping
• min tablet strength: 10-15 kp
Kamba, M., Y. Seta, A. Kusai, M. Ikeda and K. Nishimura (2000). "A unique dosage form to evaluate the
mechanical destructive force in the gastrointestinal tract." International Journal of Pharmaceutics 208: 6170.
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Low stomach pH - normal
• Stomach acid results in degradation of some
drugs
• Susceptable API are formulated with enteric
coat
– Normally dissolves at higher pH (eg 6 -7)
• Or are administered with:
– Antacids
– H2 antagonists
– Proton pump inhibitors
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Lindahl, A., A.-L. Ungell, L. Knutson, and H. Lennernas, Characterization of fluids from the
stomach and proximal jejunum in men and women. Pharm Res, 1997. 14(4): p. 497-502.
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High stomach pH - achlorhydria
• Achlorhydria (pH >5.1 in men, > 6.8 in
women1), or the administeration of antacids,
H2 antagonists, or proton pump inhibitors
raises gastric pH.
– Result: less/no dissolution of weak bases
Lower
solubility, and
slower
dissolution
Sugano, K. (2012). BIOPHARMACEUTICS MODELING AND SIMULATIONS Theory, Practice,
Methods and Applications. Hoboken, NJ, Wiley.
1. http://emedicine.medscape.com/article/170066-overview
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High stomach pH
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How can food increase exposure?
• Buffering stomach contents resulting in a
transient rise in gastric pH (weak bases)
• Solubilizing effects from bile acid & lecithin
secretion
• Increase in small intestine water volume
• Delay in gastric emptying*
*Sutton, S. C. and R. Nause (2012). Explaining the Positive Food Effect for Ziprasidone HCl Observed in the Clinic. AAPS National Meeting, Chicago, AAPS.
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How long is pH elevated?
1-2 hours
Dressman, J. B. (1986). "Comparison of canine and human gastrointestinal physiology." Pharmaceutical Research 3: 123-131.
Gastric emptying
• Impact of the pyloris and dosage form size
• Effect of food
– Calories
– Volume
– Consistency
– Fat
– Protein
– Carbohydrates
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The pyloris and dosage form size
humans
Percent Emptied (%)
120
100
80
foxhounds
60
40
20
beagles
0
0
6
12
Tim e (hr)
18
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Fix, J. A., R. Cargill and K. Engle (1993). "Controlled gastric emptying III. Gastric residence time of a nondisintegrating geometric shape in human volunteers." Pharm Res 10: 1087-1089.
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INTESTINAL
TRACT
Gall bladder & pancreatic
secretions enter the duodenum
Transit through the
duodenum is faster than
through the jejunum.
Transit through the ileum is
slower than through the
jejunum.
http://www.mymedicalfeedback.com/library/digestion-and-absorption-of-various-foods-and-nutritive-components/
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Gastric emptying and Duodenal passage of
a non-disintegrating capsule
N
S
Fasted volunteer
Supine position
Real time
Weitschies, W., R. Kotitz, D. Cordini and L. Trahms (1997). "High-Resolution Monitoring of the Gastrointestinal Transit of a Magnetically
Marked Capsule." Journal of Pharmaceutical Sciences 86(11): 1218-1222.
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Small intestine
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http://faculty.southwest.tn.edu/rburkett/A&P2%20Digestive%20System%20Lab.htm
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Intestinal Folds
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Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Intestinal Villi.
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Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Intestinal microvilli.
Glycocalyx & mucous
Tight junctions
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Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Paracellular space
Tight junctions
Cereijido, M. and J. M. Anderson (2001). Tight junctions, CRC.
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Ln2Cl3
Hochman, J. H., J. A. Fix and E. L. LeCluyse (1994). "In vitro and in vivo
analysis of the mechanism of absorption enhancement by
palmitoylcarnitine." Journal of Pharmacology and Experimental Therapeutics
269(2): 813-822.
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Tight Junctions
• Negatively charged
• 4-8 angstrom pore
diameter
• Paracellular
transport (eg
atenolol,
propranolol)
Fix, J., K. Engle, P. Porter, P. Leppert, S. Selk, C. Gardner and J. Alexander (1986). "Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal
tract." Am July
J Physiol
G332-340.
25,250:
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pH and bile acids in upper jejunum
Lindahl, A., A.-L. Ungell, L. Knutson and H. Lennernas (1997). "Characterization of fluids from the stomach and proximal jejunum in men and
women." Pharm Res 14(4): 497-502.
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Volume of water in
the small intestine
Small intestine total water volume: 100 ml
Range: 50-150ml
Schiller, C., C.-P. Frohlich, T. Giessmann, W. Siegmund, H. Monnikes, N. Hosten, and W.
Weitschies, Intestinal fluid volumes and transit of dosage forms as assessed by magnetic
resonance imaging. Aliment. Pharmacol. ther., 2005. 22: p. 971-79.
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Functions
of the
Small
Intestine.
•Mixing
•Peristalsis
•Propagation
•Absorption
•Bile acids
oSecretion into duodenum
oReabsorption from ileum
Netter, F. (1964). The Netter Collection of Medical Illustrations - Digestive System: 3-Part Set. New York, CIBA.
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Housekeeper wave (MMC)
Code, C. F. and J. A. Marlett (1975). "The interdigestive myo-electric complex of the stomach and small bowel of dogs." Journal of Physiology 246: 289-309.
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Small intestine
transit time (SITT)
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Davis, S. S., J. G. Hardy and J. W. Fara (1986). "Transit of pharmaceutical dosage forms through the small intestine." Gut 27(886-892).
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Shortened SITT when fed
Fadda, H., E. McConnell, M. Short and A. Basit (2009). "Meal-Induced Acceleration of Tablet Transit Through the Human Small Intestine." Pharmaceutical Research 26(2): 356-360.
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MMC and small intestine transit
Summers, R. W., J. Helm and J. Christensen (1976). "Intestinal propulsion in the dog. Its relation to food intake and the migratory myoelectric complex." Gastroenterology 70(5 PT.1): 753-8.
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Ileal-cecal junction
Ileocecal sphincter
http://sr.photos1.fotosearch.com/bthumb/LIF/LIF145/PED06020.jpg
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Small intestine transit of pellets & a
tablet in the same subject.
Hebden, J. M., P. J. Gilchrist, A. C. Perkins, C. G. Wilson and R. C. Spiller (1999). "Stool water content and colonic drug absorption: contrasting effects of lactulose and codeine."
Pharmaceutical Research 16(8): 1254-9.
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Small intestinal transporter proteins
• Uptake transporters
– Solute Carrier superfamily (SLC)
• OATP
• PEPT1
• MRP3
• Efflux transporters
– ATP-binding Cassette superfamily (ABC)
• MDR1 (more prevalent in jejunum & colon)
• BCRP
• MRP3
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Differences between Uptake & Efflux
transporters
Uptake transporters
• Transport along the
concentration gradient
• Do not require energy
• Located on the apical
membrane
• Enable absorption
Efflux transporters
• Transport against the
concentration gradient
• Require energy
• Located on the apical and
basolateral membranes
• Impede absorption (if
located only on the apical
membrane)
Small intestinal transporter proteins
• There are regional differences in the
distribution of both SLC and ABC transporters
along the length of the intestine and across
different species
•
•
•
•
Anderle, P. and C. Nielsen (2009). Transporters in the gastrointestinal tract. Drug Bioavailability: Estimation of Solubility,
Permeability, Absorption and Bioavailability. H. van de Waterbeemd and B. Testa. Weinheim, Wiley-VCH Verlag GmbH & Co.
KGaA: 223-276.
Stephens, R., J. Tanianis, N. Higgs, M. Humphrey and G. Warhurst (2002). "Region-dependent modulation of intestinal
permeability by drug efflux transporters: In vitro studies in mdr1a (-/-) mouse intestine." JPET 303: 1095-1101.
Hilgendorf, C., G. Ahlin, A. Seithel, P. Artursson, A.-L. Ungell and J. Karlsson (2007). "Expression of Thirty-six Drug Transporter
Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines." Drug Metabolism and Disposition 35(8): 1333-1340.
Gutmann, H., P. Hruz, C. Zimmermann, C. Beglinger and J. Drewe (2005). "Distribution of breast cancer resistance protein
(BCRP/ABCG2) mRNA expression along the human GI tract " Biochem Pharmacol 70: 695-699.
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Intestinal metabolism & extraction
• The absorptive cells lining the intestine are the
first barrier to substances that may do us
harm.
• These cells contain numerous enzymes that
metabolize substances before they can pass
on to the liver.
• These cells also contain efflux transporters
that excrete substances out of the body.
Intestinal metabolism & extraction
• The absorptive cells lining the intestine are the
first barrier to substances that may do us
harm.
• These cells contain numerous enzymes that
metabolize substances before they can pass
on to the liver.
• These cells also contain efflux transporters
that excrete substances out of the body.
Intestinal enzymes
• Cytochrome p450 isozymes
– CYP3A4
– CYP2C9
• Glucorono-syl-transferases
• Alcohol dehydrogenase
Cytochrome p-450 isozymes
• CYP3A4
– 80% of the total intestine CYP
• CYP2C9
– 15% of the total intestine CYP
CYP3A4
• Most important intestinal extraction process:
Many drugs are substrates
• Levels are highest in upper small intestine
(duodenum)
• Levels decrease progressively to the distal
ileum
• Wide interindividual variability in expression
– Results in wide variability in drug bioavailability
CYP3A4
• Low concentration relative to liver (1%)
• Regardless, can be responsible for
metabolizing a substantial amount of oral
dose
• The intestinal enzymes remove ≥50% of the
oral dose of:
– Tacrolimus, buspirone, atorvastatin, cyclosporine
Synergy with P-gp
• Many drugs that are substrates for CYP3A4 are
also substrates of P-gp
• Efflux by P-gp and subsequent reabsorption
– Prolongs the API contact with the cells’ enzymes
Small intestinal metabolism
• Species differences in gut metabolism may
confuse the interpretation of PK results with
CR formulations
•
•
Chauret, N., A. Gauthier, J. Martin and D. A. Nicoll-Griffith (1997). "In Vitro Comparison of Cytochrome P450-Mediated
Metabolic Activities in Human, Dog, Cat, and Horse." Drug Metabolism and Disposition 25(10): 1130-1136.
Straw, J. A., T. L. Loo, C. C. deVera, P. D. Nelson, W. A. Tompkins and S. A. Bai (1992). "Pharmacokinetics of Potential Anti-AIDS
Agents Thiofoscarnet and Foscarnet in the Cat." JAIDS Journal of Acquired Immune Deficiency Syndromes 5(9): 936-942.
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Colon: the large intestine
• Shorter than the small intestine
• Much larger diameter
• Water content
– Ascending: ~10 mls (fasted) 180 mls (fed)
as viscous mush
– Transverse: none (mostly gas)
– Descending: none (storage)
• Functions:
– water absorption
– some nutrient absorption (fatty acids)
– storage
http://www.loveyourcolon.org/sites/default/files/digestivetrack.jpg
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Transit of a nondisintegrating capsule
through the transverse colon.
male volunteer
supine position,
6 h after ingestion
real time
Weitschies, W., R. Kotitz, D. Cordini and L. Trahms (1997). "High-Resolution Monitoring of the Gastrointestinal Transit of a Magnetically
Marked Capsule." Journal of Pharmaceutical Sciences 86(11): 1218-1222.
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Summary
• Esophagus
– Transports food and medication from the oral cavity to the stomach
• Stomach
Controls delivery of its contents to the small intestine
– grinds contents
– pH may be elevated due to disease, medication
–
• Small intestine
– Digestion & absorption
– Mixing with bile acids, lecithin forms micelles
– Housekeeper wave or MMC
• Every 2 hours unless fed
– ~100 mls water
– Duodenum
• Rapid transit
• Bile acids & enzymes enter
• Most active uptake transport/absorption and metabolism
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Summary (continued)
• Jejunum
– Most nutrient absorption occurs here
– Most passive absorption
• Ileum
– Small intestine contents are often delayed at the ileal-cecal junction before
entering the colon
– Bile acids absorbed
• Colon – water absorption
–
–
–
–
–
–
–
Neutral pH
Ascending may have water
Transverse contains gas
Descending is primarily storage
Some reducing bacteria may degrade susceptible API
Diffusion of API from dosage forms drops considerably as water is absorbed
Higher levels of efflux transporters
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[email protected]
Dr. Steven (Steev) C. Sutton B.S. Pharmacy, Ph.D.
Associate Professor of Biopharmaceutics, Pharmacokinetics and Physical Pharmacy
Chair, Department of Pharmaceutical Sciences
College of Pharmacy
University of New England
716 Stevens Ave.
Portland, ME 04103
207-221-4173 Office
860-271-1369 Mobile
207-523-1926 Fax
http://www.une.edu/faculty/profiles/ssutton1.cfm
http://www.imdb.com/title/tt0325980/quotes?qt=qt0416730
Pharmaceutical Sciences. Yes. It's good here.
Thank you!
Questions?
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