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Effect of gastrointestinal maturation on absorption of beta-lactam antibiotics
E Morita1, N Mizuno, M Nishikata
1Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
Insights
Young rats absorb cefazolin differently than adults, with absorption decreasing significantly after weaning. This suggests immature intestinal permeability is key for cefazolin uptake in pre-weaned rodents.
Area of Science:
- Pharmacology
- Developmental Biology
- Gastroenterology
Background:
- Cefazolin is poorly absorbed orally in adult humans, while cephradine is well absorbed.
- Understanding developmental changes in gastrointestinal absorption is crucial for pediatric drug dosing.
Purpose of the Study:
- To investigate the developmental changes in gastrointestinal absorption of cefazolin and cephradine in rats.
- To elucidate the mechanisms underlying age-dependent differences in cefazolin absorption.
Main Methods:
- Oral administration of cefazolin and cephradine to rats of different ages (1, 2, 3 weeks, and adults).
- Measurement of plasma drug concentrations.
- In situ jejunal uptake studies and in vitro uptake experiments.
- Administration of cortisone to assess its effect on intestinal maturation and drug absorption.
Main Results:
- Significantly higher plasma cefazolin concentrations were observed in 1- and 2-week-old rats compared to older rats.
- Cefazolin absorption showed a developmental pattern linked to intestinal maturation, decreasing after weaning.
- Cortisone treatment in young rats reduced cefazolin plasma levels and jejunal uptake.
- Cephradine absorption did not show significant age-dependent differences and exhibited saturable kinetics, unlike cefazolin's non-saturable absorption.
Conclusions:
- Gastrointestinal absorption of cefazolin in young rats is dependent on intestinal membrane permeability before weaning.
- Cefazolin absorption appears to follow a non-saturable pathway, while cephradine absorption is saturable and potentially carrier-mediated.
Abstract:
Gastrointestinal absorption of cefazolin, which is poorly absorbed in adults, and of cephradine, which is well absorbed in adults, was studied in rats during their development. Significantly higher concentrations of cefazolin in plasma after oral administration were observed in 1- and 2-week-old rats compared with 3-week-old and adult rats. A marked difference in the absorption of cefazolin by 2- and 3-week-old rats (at weaning period) was observed. No such marked difference in the absorption of cephradine by rats of various age groups was found. With cefazolin, a similar pattern of developmental change in jejunal uptake was observed. Cortisone, which causes early maturation of the intestinal membrane, was given as a preweaning injection to 2-week-old rats. This treatment decreased concentrations of cefazolin in plasma and jejunal uptake of cefazolin. Thus, the absorption of cefazolin in 1- and 2-week-old rats seems to depend on the permeability of the immature intestinal membrane before weaning. Cephradine absorption from the intestine of 1-week-old rats became saturated and inhibited by carnosine and glycylglycine when studied by the in situ loop method. Cefazolin absorption was proportional to luminally administered doses and was not affected by carnosine and glycylglycine. A nonsaturable process for cefazolin and a saturable process for cephradine were also observed in an in vitro uptake experiment.