Altered systemic bioavailability and organ distribution of azathioprine in methotrexate-induced intestinal mucositis in rats.
OBJECTIVE
Intestinal mucositis is a significant problem haunting clinicians for decades. One of the major reasons for its occurrence is high-dose chemotherapy. The study is aimed at investigating effect of intestinal mucositis on pharmacokinetics, organ distribution, and bioavailability of azathioprine (AZA) (6-mercaptopurine).


METHODS
Intestinal mucositis was induced with methotrexate (MTX) (2.5 mg/kg). The oral absorption of AZA and 6-mercaptopurine (metabolite) levels were determined in control and MTX-treated rats: ex vivo (noneverted sac technique) and in vivo (pharmacokinetics and organ-distribution) using high-performance liquid chromatography. Immunohistochemistry was conducted to evaluate peptide transporter expression on luminal membrane of small intestine.


RESULTS
Intestinal permeation of AZA into systemic circulation of rats was lower after MTX administration, widely found in intestinal segments of mucositis-induced rats leading to decline in systemic bioavailability of AZA. Immunohistochemistry findings indicated diminution of peptide transporter expression representing hampered absorption of drugs absorbed via this transporter.


CONCLUSIONS
Study outcome has thrown light on altered fate of AZA when administered to individuals with mucositis which suggests modified drug therapy. These findings can further be investigated in different drug classes which might be administered concomitantly in mucositis and study outcome can be further confirmed in mucositis patients in clinical practice also.
Department of Pharmacology, Bombay College of Pharmacy, Mumbai, Maharashtra, India.
Sadaf A
SA
Karbelkar
Department of Pharmacology, Bombay College of Pharmacy, Mumbai, Maharashtra, India.
Anuradha S
AS
Majumdar
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001379:Azathioprine / Q000493:pharmacokinetics*; D001682:Biological Availability; D001835:Body Weight; D002956:Citrulline / Q000097:blood; D004751:Enteritis / Q000139:chemically induced*; D005247:Feeding Behavior; D005978:Glutathione / Q000097:blood; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D002956:Citrulline; D009195:Peroxidase; D005978:Glutathione; D001379:Azathioprine; D008727:Methotrexate
Azathioprine; bioavailability; intestinal mucositis; organ-distribution; pharmacokinetics