Prediction of the plasma concentration profiles of orally administered drugs in rats on the basis of gastrointestinal transit kinetics and absorbability

J Pharm Pharmacol. 1997 Apr;49(4):450-7. doi: 10.1111/j.2042-7158.1997.tb06823.x.

Abstract

A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats. The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems. We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.

MeSH terms

  • Administration, Oral
  • Ampicillin / administration & dosage
  • Ampicillin / blood
  • Ampicillin / pharmacokinetics
  • Animals
  • Area Under Curve
  • Biological Availability
  • Cephalexin / administration & dosage
  • Cephalexin / blood
  • Cephalexin / pharmacokinetics
  • Cephalosporins / administration & dosage
  • Cephalosporins / blood
  • Cephalosporins / pharmacokinetics
  • Chromatography, High Pressure Liquid
  • Gastrointestinal Transit / physiology*
  • Intestinal Absorption / physiology*
  • Male
  • Penicillins / administration & dosage
  • Penicillins / blood
  • Penicillins / pharmacokinetics
  • Pharmacokinetics*
  • Phenolsulfonphthalein / chemistry
  • Propranolol / administration & dosage
  • Propranolol / blood
  • Propranolol / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Theophylline / administration & dosage
  • Theophylline / blood
  • Theophylline / pharmacokinetics
  • Vasodilator Agents / administration & dosage
  • Vasodilator Agents / blood
  • Vasodilator Agents / pharmacokinetics

Substances

  • Cephalosporins
  • Penicillins
  • Vasodilator Agents
  • Ampicillin
  • Propranolol
  • Theophylline
  • Phenolsulfonphthalein
  • Cephalexin