Web Hosting by Netfirms | Free Domain Names by Netfirms

DRUG ABSORPTION AFTER ORAL ADMINISTRATION

Generally, disintegration and dissolution are the rate-limiting steps in the absorption process.

Dissolution - described by Noyes-Whitney equation.

dc	=	K.S. (C - C)
_____
dt

Factors Influencing Oral Bioavailability (See R & T Chapter 3):

1. Formulation factors:

(a) Physiochemical properties of drug.

(b) Manufacturing (dosage form) properties.

2. Physiological (patient-related) factors.

 

1. Formulation Factors:

(a) Physiochemical properties of drug:

(i) Water solubility/Ko/w (lipid solubility):

Eg. Poor water solubility

Digoxin
Spironolactone 
Griseofulvin

Eg. Poor lipid solubility

Neomycin 

(ii) pKa (pH partition theory):

Main relevance is to dissolution, rather than absorption because of “sink” conditions.

Practical implications:

Water soluble drugs
Weakly basic drugs 

Absorption is not usually limited by dissolution (gastric emptying is more important)

Weakly acidic drugs:-

C	=	[HA]	+	[A]
	.
	=	[HA]	+	[HA] ka
				________
				[H]
	.
	=	Co	+	Co . Ka
				________
				[H]

 

		[H] + [A]
Ka	=	__________
		[HA]

Co = Intrinsic solubility

Cs with pH for weak acids.

 

pH partition theory (approx. 1960):

- Most drugs are absorbed by passive diffusion.

- The GI membrane acts like a semi-permeable lipoid barrier.

- The absorption of a drug is almost solely due to the absorption of its unionised form.

- Weak bases dissolve faster in the gastric fluids and weak acids dissolve faster in the intestinal fluids.

- Hence, the efficiency of absorption of a weakly acidic or basic drug will change as the dosage form passes through various pH conditions in the GIT, under the influence of the pK and lipid solubility of the drug.

- NB Because of large surface area of small intestine and “sink conditions”, the pH partition theory’s main relevance is to the process of dissolution, rather than to absorption through GI membranes.

Eg: Salicylate (pK about 3).

Isolated stomach: 30% absorbed in 1 hour.
Intestines: 60% absorbed in 10 mins.

Ie: Absorbed faster from intestines even though more ionised.

- Therefore, to increase the dissolution rate of weak acids, increase the pH of the diffusion layer.

- Administer with an antacid (Eg. Bufferin - buffered aspirin tablets).

- Use a water soluble salt of the weak acid, which will act as its own buffer. The sodium or potassium salts of weak acids dissolve more rapidly than the free acids, regardless of the pH of the dissolution medium.

Stomach:

A + H HA

Intestine:

AH + OH A + H2O

 

(iii) Polymorphism:

Eg: 

Insulin
Novobiocin

 

(iv) Solvent addition compounds (solvates):

 

(v) Particle size/surface area:

dc	=	K.S. (C - C)
_____
dt

Eg: 

Griseofulvin
Spironolactone

NB: Particle size reduction is not always successful in improving bioavailability.

 

(vi) Drug stability in GI fluids:

Eg: Benzylpenicillin.

 

(vii) Complexation:

 

(b) Manufacturing (dosage form) factors:

Normally,

Solutions > suspensions > capsules > tablets > coated tablets.

Solutions:

Rapid and predictable absorption.

Suspensions:

Capsules:

Tablets:

Influence of: Other ingredients (R & T, page 20), eg. Binder.
Manufacturing procedures, eg. compression pressure.
[See Practical No. 2].

Coated Tablets:

Most unpredictable, eg. enteric coated Aspirin.

 

2. Physiological (Patient-Related) Factors:

(i) Food intake:

- Effects are complex and not readily predictable.

- Bioavailability may or or .

- Changes in GI motility, splanchnic blood flow, GI secretions. Also, food-drug complexation possible.

NB The composition and volume of the meal are also important determinants of the effect on drug bioavailability.

TABLE: Influence of Diet on the Bioavailability of Drugs
	Bioavailability Relative to Intake in the Fasting State
	Carbohydrate Rich		Protein Rich		Lipid Rich
Drug	(Rate)	(Extent)	(Rate)	Extent)	(Rate)	(Extent)	Reference
Acetaminophen	-		(-)		/	/	(231)
Acetylsalicylic acid	--		-	%	-	+	(232)
Amoxicillin	-	-	-	-	-	-	(73)
Ampicillin	-	-	-	-	-	-	(73)
Clofibrate	+		++				(55, 56)
Digitoxin	-		-		-		(146)
Doxycycline					(-)		(86)
Erythromycin stearate	()	-	()	-	()	-	(94)
Ethanol	()	--	()	-	()	-	(96)
Griseofulvin	/	/	(+)	(+)	++	++	(207, 208)
Indomethacin	-		(-)		-		(156)
Nitrofurantoin	(-)				(+)		(55, 174)
Propoxyphene	-	(+)	-		(-)		(224)
Sodium salicylate	-		/	/	-	()	(52, 170)
The following symbols are used in the table:- + = improved; - = decreased; = not affected; () = questionable.

- Food-drug complexation, eg. Tetracyclines, but not Doxycycline.

Clinical implications:

Eg. Mclean and Melander.
Australian Prescriber 1986; Vol 9. (3) page 68.

(ii) Fluid intake:

100-250ml water recommended.

(iii) Gastric emptying:

- Most drugs are best absorbed from the small intestine.

- Particularly important for:-

- EC dosage forms.
- Drugs unstable in GI fluids.

(iv) First-pass metabolism:

Splanchnic circulation (receives ~ 28% of cardiac output) drains into the portal vein which flows to the liver.

“First-pass” Effect:

Drugs Undergoing Substantial First-Pass Metabolism
Amitriptyline	Isoprenaline	Pentazocine
Aspirin	Isosorbide dinitrate	Pethidine
Chlormethiazole	Labetalol	Praziquantel
Chlorpromazine	Levodopa	Prazosin
Dextropropoxyphene	Lignocaine	Propranolol
Dihydroergotamine	Meptazinol	Salbutamol
Domperidone	Methylphenidate	Terbutaline
Doxepin	Metoprolol	Verapamil
Glyceryl trinitrate	Morphine
Imipramine	Nortriptyline
Indoramin	Oral contraceptives

(v) Posture and physical activity:

Supine position:

- Co.

- Hepatic and renal blood flow.

- Gastric emptying (esp. on left side).

Variable effects.

Physical activity:

- SNS tone.

- Splanchnic blood flow (including liver).

- Gastric emptying.

Influence of the Supine Position on the Bioavailability of Drugs¶
	Bioavailability
Drug	Rate	Extent	References
Acetaminophen	-§		(290)
Acetylsalicylic acid	-	()	(291)
Cephradin	-	()	(292)
Fenoprofen	-	()	(98)
Phenazone	+	(-)	(293)
Sodium salicylate	-	-	(52, 170)
Sulfacarbamide	()	-¤	(52, 170)
Sulfisomidine	()	-	(52, 170)
Tolbutamide	()	-¤	(52, 170)
¶ The following symbols are used in the table:-  + = improved; - = decreased; = not affected; () = questionable.  § Reduced lag-time.  ¤ In the fasting state or with a light breakfast.

 

Influence of Physical Activity/Exercise on the Bioavailability of Drugs¶
	Bioavailability
Drug	Rate	Extent	References
Acetylsalicylic acid			(128)
Antipyrine	+		(295)
Atenolol		(+)	(298)
Benzylpenicillin	+		(299)
Diazepam	+		(300)
Doxycycline	+		(297)
Sulfamethiazole	+		(297)
Sulfaperine	(-)§		(55, 56, 174)
Tetracycline	+		(297)
Vitamin A	()	-	(301)
¶ The following symbols are used in the table:-  + = improved; - = decreased; = not affected; () = questionable.  § Prolongation of lag-time.  ¤ By comparison with cumulative renal elimination.

 

(vi) Drug-food and drug-drug interactions:

- Gastric emptying.

- GI secretions.

- Competition with dietary components.

- Absorption of drug.

- Physiochemical interaction.

 

(vii) Disease states:

- Achlorhydria.

- Crohn’s disease.

- Coeliac disease.

- Chronic liver disease.

 

(viii) Individual variability:

- Intra-patient.

- Inter-patient.

Conclusions: