title: WHR 1049, a potent metabolite of lidamidine, has antidiarrheal and antimotility effects on the small intestine in rats.
abstract: Lidamidine HCl has been suggested to be effective in treating certain motor disorders of the gastrointestinal tract. Lidamidine has alpha-2 agonist as well as local anesthetic properties. We studied the antimotility and antidiarrheal activity of WHR 1049, a hepatic metabolite of lidamidine known to have some activity and to persist longer in the serum than does lidamidine. We recorded the intestinal myoelectric activity of fasted unanesthetized rats with bipolar electrodes implanted on their proximal jejunum. We found that lidamidine HCl, given by gavage, inhibited fasting myoelectric activity in a dose-dependent manner (using 0.5-4.0 mg/kg). Neither saline nor tetracaine inhibited myoelectric activity. WHR 1049 given by gavage also inhibited myoelectric activity and was 30 times as potent as lidamidine (milligram per milligram, using 0.0625- to 0.25-mg/kg doses). Pretreatment with yohimbine (5 mg/kg s.c.), before administration of WHR 1049, decreased the myoelectric activity inhibition by two-thirds (but did not completely block it). Castor oil (1 ml/200 g b.wt.) was given to induce diarrhea and did so when given alone or with saline (vehicle) pretreatment. When these animals were pretreated with 0.25 mg/kg of WHR 1049, the same dose of castrol oil did not induce diarrhea for a 6-hr observation period. We conclude that WHR 1049 is a potent metabolite of lidamidine that inhibits myoelectric activity, has significant alpha-2 agonist activity and blocks induced diarrhea. Because tetracaine does not inhibit myoelectric activity we suggest that the local anesthetic properties of lidamidine do not account for any of the myoelectric activity inhibition. WHR 1049 may account for much of the antimotility and antidiarrheal activity of lidamidine.
authors.affiliation: Department of Medicine, College of Medicine, University of Florida, Gainesville.
authors.forename: E Y
authors.initials: EY
authors.lastname: Eaker
authors.forename: G B
authors.initials: GB
authors.lastname: Bixler
authors.forename: J R
authors.initials: JR
authors.lastname: Mathias
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000930:Antidiarrheals; D002368:Castor Oil; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013748:Tetracaine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000930:Antidiarrheals; D010671:Phenylurea Compounds; D013748:Tetracaine; D015016:Yohimbine; C056846:WHR 1049; D002368:Castor Oil; C020918:lidamidine