title: Effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition.
abstract: Protein-calorie malnutrition (PCM) could occur frequently in cancer patients and alter the pharmacokinetics of drugs. Also cysteine shows anti-oxidative effect and changes the activities of drug metabolizing enzyme and/or transporters. Herein, we investigated the effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition (PCM).        The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of tamoxifen were assessed using control, CC (control with cysteine), PCM, PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of tamoxifen were further investigated through in vitro transport studies using rat intestine.        The AUCs of intravenous tamoxifen in PCM rats were significantly greater than control rats due to the decrease in the hepatic metabolism via CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels by oral cysteine supplement. The AUC of oral tamoxifen in PCM rats was significantly smaller than in control rats mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of tamoxifen probably via intestinal P-gp inhibition.        The present study demonstrated that PCM state and/or oral cysteine supplement had a profound impact on the pharmacokinetics of tamoxifen in rats. If the present rat data are extrapolated to humans, the alterations in tamoxifen absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM and/or oral cysteine supplement.
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Siksa-dong, Ilsandong-gu, Goyang, Gyeonggi-do, South Korea.
authors.forename: Yu Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Insoo
authors.initials: I
authors.lastname: Yoon
authors.forename: Myung Gull
authors.initials: MG
authors.lastname: Lee
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Choi
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology / Q000627:therapeutic use*; D003956:Dialysis; D002149:Energy Intake / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011502:Protein-Energy Malnutrition / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D013629:Tamoxifen; D003545:Cysteine