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Decrease in protein binding and its effect on toxicokinetics (TK)/toxicodynamics (TD) of diclofenac and propranolol
Hiroaki Miida1, Yumiko Noritake, Hitomi Shimoda
1Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. miida.hiroaki.vg@daiichisankyo.co.jp
The Journal of Toxicological Sciences
|December 2, 2008
Summary
Pregnancy alters drug binding, increasing free diclofenac and propranolol levels. This leads to higher drug exposure and potentially greater toxicity in pregnant rats compared to non-pregnant ones.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Toxicology
- Reproductive Biology
Background:
- Plasma protein binding is crucial for drug distribution and action.
- Pregnancy-induced physiological changes can alter drug binding and response.
- Understanding these changes is vital for safe medication use during pregnancy.
Purpose of the Study:
- To investigate the toxicokinetics and toxicodynamics of diclofenac and propranolol in pregnant versus non-pregnant rats.
- To compare drug distribution and protein binding in pregnant and non-pregnant Sprague-Dawley rats.
- To elucidate the impact of pregnancy on drug disposition and toxicity.
Main Methods:
- Comparison of toxicokinetics (TK) and toxicodynamics (TD) between pregnant and non-pregnant Sprague-Dawley rats.
- Administration of diclofenac and propranolol, drugs binding to albumin and alpha(1)-acid glycoprotein (AGP) respectively.
- Analysis of plasma protein binding, drug distribution (Area Under the Curve - AUC), and histopathological examination for toxicity.
Main Results:
- Pregnant rats showed a 3.9-fold higher AUC for free diclofenac, attributed to lower albumin and higher non-esterified fatty acid (NEFA) concentrations.
- More severe gastrointestinal toxicity was observed in pregnant rats, correlating with higher diclofenac AUC.
- While AGP was lower in pregnant rats, free propranolol AUC differences were unclear, though binding analysis suggested altered binding at lower concentrations.
Conclusions:
- Lowered serum proteins and increased NEFA in pregnant rats significantly reduce protein binding.
- This reduction in binding leads to increased free drug concentrations.
- Consequently, pregnant rats exhibit an elevated toxicodynamic response to the studied drugs.
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