title: Effect of intestinal atrophy and hepatic impairment induced by parenteral nutrition on drug absorption and disposition in rats.
abstract: BACKGROUND
  Long-term parenteral nutrition (PN) has a high risk of hepatic dysfunction and intestinal atrophy. The present study investigated the effect of PN-induced intestinal atrophy and hepatic impairment on drug pharmacokinetics by using 2 contrasting compounds: phenolsulfonphthalein (PSP) and cyclosporin A (CyA).
  
  
  METHODS
  PSP or CyA was administered to 7-day PN-fed Rats (PN rats) and sham operated rats (control rats) via intravenous (IV) or intraloop administration of the intestine. Pharmacokinetic parameters with 2-compartment analysis including area under the concentration vs time curve (AUC) and the permeability after in situ intraloop administration (P loop) were obtained from both concentration profiles after different administration routes.
  
  
  RESULTS
  After IV administration of PSP to control and PN rats, there was no notable difference in any of the pharmacokinetic parameters. In contrast, after intraloop administration, AUC and P loop in PN rats were approximately 2.6- and 2.0-fold higher than that in control rats, respectively. On the other hand, after IV administration of CyA, the terminal half-life and total body clearance were prolonged and decreased in PN rats, respectively, resulting in 2.0-fold increase in AUC. After intraloop administration, the AUC of PN rats was increased to approximately 1.3-fold that of control rats, whereas no notable difference was observed in P loop.
  
  
  CONCLUSIONS
  The intestinal permeability of PSP was enhanced by intestinal atrophy induced by PN, while the metabolism of CyA was diminished by hepatic impairment by PN. These results revealed the physicochemical property-based pharmacokinetic alterations during PN; for a more detailed understanding, however, further studies are needed.
authors.affiliation: Department of Clinical Pharmacokinetics, Kobe Gakuin University, Hyogo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Department of Clinical Pharmacokinetics, Kobe Gakuin University, Hyogo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miki
authors.affiliation: Department of Clinical Pharmacy, Kobe Gakuin University, Hyogo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.affiliation: Department of Biopharmaceutics, Doshisha Women's College of Liberal Arts, Kyoto, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Department of Physical Pharmacy, Kobe Gakuin University, Hyogo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Department of Biopharmaceutics, Doshisha Women's College of Liberal Arts, Kyoto, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Department of Clinical Pharmacy, Kobe Gakuin University, Hyogo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
authors.affiliation: Department of Clinical Pharmacokinetics, Kobe Gakuin University, Hyogo, Japan nsugioka@pharm.kobegakuin.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D001284:Atrophy / Q000209:etiology; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010288:Parenteral Nutrition / Q000009:adverse effects*; D010539:Permeability / Q000187:drug effects; D010637:Phenolsulfonphthalein / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D016572:Cyclosporine; D010637:Phenolsulfonphthalein
keywords: absorption; bioavailability; intestinal atrophy; parenteral nutrition; pharmacokinetics