Chapter 11 Physiological Factors Affecting Oral Absorption

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Gastrointestinal (GI) Physiology

Characteristics of GI physiology

Table 11.3.1 GI Physiology and Drug Absorption Washington et al., 2001

pH Membrane Blood Supply Surface Area Transit Time By-pass liver

BUCCAL approx 6 thin Good, fast absorption with low dose small Short unless controlled yes

ESOPHAGUS 6-7 Very thick, no absorption - small short, typically a few seconds, except for some coated tablets -

STOMACH 1.7-4.5
decomposition, weak acid unionized normal good small 30 min (liquid) - 120 min (solid food), delayed stomach emptying can reduce intestinal absorption no

DUODENUM 5 - 7
bile duct, surfactant properties normal good very large very short (6" long), window effect no

SMALL INTESTINE 6 -7 normal good very large 10 - 14 ft, 80 cm ² /cm about 3 hours no

LARGE INTESTINE 6.8 - 7 - good not very large 4 - 5 ft long, up to 24 hr lower colon, rectum yes

Gastric emptying and motility

Figure 11.3.1 Dependence of Peak Acetaminophen Plasma Concentration as a Function of Stomach Emptying Half-life

Redrawn from Heading, R.C., Nimmo, J., Prescott, L.F. and Tothill, P. 1973.
The dependence of paracetamol absorption on the rate of gastric emptying,
Br. J. Pharmacol., 47, 415-421

Generally drugs are better absorbed in the small intestine (because of the larger surface area) than in the stomach, therefore quicker stomach emptying will increase drug absorption. For example, a good correlation has been found between stomach emptying time and peak plasma concentration for acetaminophen. The quicker the stomach emptying (shorter stomach emptying time) the higher the plasma concentration, Figure 11.3.1.

Also slower stomach emptying can cause increased degradation of drugs in the stomach's lower pH; e.g. l-dopa.

Table 11.3.2 Factors Affecting Gastric Emptying

Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to empty more slowly than liquids

Type of Meal

Fatty food Decrease

Carbohydrate Decrease

Temperature of Food Increase in temperature, increase in empyting rate

Body Position Lying on the left side decreases emptying rate. Standing versus lying (delayed)

Drugs

Anticholinergics (e.g. atropine), Narcotic (e.g. morphine, alfentanil), Analgesic (e.g. aspirin) Decrease

Metoclopramide, Domperidone, Erythromycin, Bethanchol (see Gastroparesis ref below) Increase

From Mayersohn, M. 1971.
Physiological Factors Influencing Drug Absorption,
Can. Pharm. J., 164-169

Effect of Food

Figure 11.3.2 Effect of Fasting versus Fed on Propranolol Concentrations

Melander, A., Danielson, K., Schersten, B. and Wahlin, E. 1977.
Enhancement of the bioavailability of propranolol and metaprolol by food,
Clin. Pharmacol. Ther., 22, 108-112

Food can effect the rate of gastric emptying. For example fatty food can slow gastric emptying and retard drug absorption. Generally the extent of absorption is not greatly reduced. Occasionally absorption may be improved. Griseofulvin absorption is improved by the presence of fatty food. Apparently the poorly soluble griseofulvin is dissolved in the fat and then more readily absorbed.

Propranolol plasma concentrations are larger after food than in fasted subjects. This may be an interaction with components of the food.

Other factors

Intestinal Motility and Transit Time (Mayersohn, 1971)

Food Retards transit

Some items to consider

Item 1. The larger surface area of the small intestine means that many drugs are much better absorbed from this region of the GI tract compared with from the stomach. For some drugs the rate of absorption from the stomach is so low that stomach emptying time or rate controls the rate of absorption of the drug. For acetaminophen (paracetamol) the rate if absorption from the stomach is so slow relative to the absorption from the intestine that time of peak absorption or peak concentration after oral administration can be used to determine stomach emptying rate. (Petring and Blake, 1993)

First try simulating concentration versus time after an Oral Dose: Dose = 250 mg; kel = 0.10 hr^-1; ks = 0.12 hr^-1; ke = 1.4 hr^-1; ki = 2.1 hr^-1; V = 24 L. This ke value represents a stomach emptying time of 30 minutes (0.5 hr). Compare this line with lines generated with slower stomach emptying, that is, lower ke values. Plot Cpmax (or tmax) versus stomach emptying half-life. Explore the problem as a Linear Plot - Interactive graph

Figure 11.3.1 One Compartment Model with Absorption from Stomach and Intestine

The equations for this model after Oral Absorption was developed using Laplace transforms.

References

Heading, R.C., Nimmo, J., Prescott, L.F. and Tothill, P. 1973. The dependence of paracetamol absorption on the rate of gastric emptying, Br. J. Pharmacol., 47, 415-421
Mayersohn, M. 1971. Physiological Factors Influencing Drug Absorption, Can. Pharm. J., 164-169
Melander, A., Danielson, K., Schersten, B. and Wahlin, E. 1977. Enhancement of the bioavailability of propranolol and metaprolol by food, Clin. Pharmacol. Ther., 22, 108-112
Petring, O.U. and Blake, D.W. Gastric Emptying in Adults: An Overview Related to Anaesthesia, Anaesth Intensive Care. 1993 Dec;21(6):774-81
Washington, N., Washington, C. and Wilson, C.G. 2001 Physiological Pharmaceutics, Barriers to Drug Absorption, 2nd., Taylor & Francis

Student Objectives for this Chapter

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	pH	Membrane	Blood Supply	Surface Area	Transit Time	By-pass liver
BUCCAL	approx 6	thin	Good, fast absorption with low dose	small	Short unless controlled	yes
ESOPHAGUS	6-7	Very thick, no absorption	-	small	short, typically a few seconds, except for some coated tablets	-
STOMACH	1.7-4.5 decomposition, weak acid unionized	normal	good	small	30 min (liquid) - 120 min (solid food), delayed stomach emptying can reduce intestinal absorption	no
DUODENUM	5 - 7 bile duct, surfactant properties	normal	good	very large	very short (6" long), window effect	no
SMALL INTESTINE	6 -7	normal	good	very large 10 - 14 ft, 80 cm ² /cm	about 3 hours	no
LARGE INTESTINE	6.8 - 7	-	good	not very large 4 - 5 ft	long, up to 24 hr	lower colon, rectum yes

Volume of Ingested Material	As volume increases initially an increase then a decrease. Bulky material tends to empty more slowly than liquids
Type of Meal
Fatty food	Decrease
Carbohydrate	Decrease
Temperature of Food	Increase in temperature, increase in empyting rate
Body Position	Lying on the left side decreases emptying rate. Standing versus lying (delayed)
Drugs
Anticholinergics (e.g. atropine), Narcotic (e.g. morphine, alfentanil), Analgesic (e.g. aspirin)	Decrease
Metoclopramide, Domperidone, Erythromycin, Bethanchol (see Gastroparesis ref below)	Increase