title: Decrease in protein binding and its effect on toxicokinetics (TK)/toxicodynamics (TD) of diclofenac and propranolol in pregnant rats.
abstract: Plasma protein binding is an important factor for the kinetics of drugs and how they act since it is the first step in drug distribution. Physiological changes in pregnancy, which include plasma composition, can affect drug binding and subsequent drug response. In the present study, we investigated the toxicokinetics (TK) and/or toxicodynamics (TD) of diclofenac and propranolol comparing pregnant Sparague-Dawley (SD) rats with non-pregnant SD rats in terms of protein binding and drug distribution. Diclofenac and propranolol are reported to bind to albumin and alpha(1)-acid glycoprotein (AGP), respectively. After a single administration of diclofenac, the area under plasma concentration-time curve (AUC) based on free diclofenac in pregnant rats was 3.9 times higher than that in non-pregnant rats. This difference is considered to be due to a lower concentration of serum albumin and a higher concentration of non-esterified fatty acid (NEFA) that inhibits drug binding to albumin, in pregnant rats. In histopathological examination, more severe gastrointestinal toxicity was observed in pregnant rats at 24 hr after dosing. This severe toxicity was likely to be correlated with the higher AUC. With respect to propranolol, the difference of the AUC based on free propranolol was not clear although the concentration of serum AGP was lower in pregnant rats. However, the binding analysis data suggested a difference of protein binding at a lower propranolol concentration range. Consequently, lowered serum proteins and increased NEFA in pregnant rats can lead to low protein binding, subsequent increase in free drug concentrations, and eventual increase in the TD of drugs.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. miida.hiroaki.vg@daiichisankyo.co.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miida
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Noritake
authors.forename: Hitomi
authors.initials: H
authors.lastname: Shimoda
authors.forename: Kumi
authors.initials: K
authors.lastname: Honda
authors.forename: Toshiki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Ken
authors.initials: K
authors.lastname: Sakurai
authors.forename: Makoto
authors.initials: M
authors.lastname: Shirai
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004008:Diclofenac / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D010953:Plasma Volume; D011247:Pregnancy / Q000097:blood* / Q000378:metabolism; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D018675:Toxicity Tests
chemical_list: D001798:Blood Proteins; D004008:Diclofenac; D011433:Propranolol