Tissue distribution of the low molecular weight heparin, tinzaparin, following administration to rats by the oral route.
Heparins are antithrombotic drugs given by intravenous and subcutaneous routes. However, we have observed that heparins have antithrombotic activity in a rat model when administered orally despite low plasma levels, with low molecular weight heparins (LMWHs) being effective at lower single doses than unfractionated heparins (UFH). Since LMWHs may have other pharmaceutical uses and little is known regarding the pharmacokinetics of oral LMWHs, our objectives were to determine the distribution of the LMWH tinzaparin (Logiparin) following oral dosing. To study distribution at different doses, 0.025-15 mg/kg tinzaparin was given by stomach tube to rats. Gut and non-gut tissues were sampled 4 h later. In a time course study, plasma and tissue samples were collected at eight time points within 24 h after oral administration (60 mg/kg, 4 rats/time interval). Accumulated urine and faeces were collected over 4 and 24 h using metabolic cages. Gut tissue and washes, faeces, urine and non-gut tissue were extracted and analysed for heparin by agarose gel electrophoresis with toluidine blue staining. Activated partial thromboplastin time (APTT) and anti-Xa activity, by Heptest and chromogenic assay, estimated plasma tinzaparin concentrations. Stomach and lung tinzaparin concentrations demonstrated a dose-effect. Peak concentrations in tissue and washes of stomach, duodenum, jejunum, ileum and colon were at 6-30, 15-30, 30 min, 2 and 4 h, respectively. Amounts found at peak times in combined tissue and washes accounted for 46% and 0.5% in stomach (15 min) and colon (4 h), respectively. Tinzaparin was recovered from liver, lung, endothelial samples, and urine at 24 h, but not in faeces. Non-significant increases were seen in APTT and the Heptest, however, anti-Xa activity was significantly greater than control at all times examined, peaking at 2 h. No bleeding was observed. Results are consistent with oral absorption of tinzaparin with wide tissue distribution, likely on endothelium with little in plasma, as previously observed for UFH. Oral administration of LMWHs should be further studied.
Hiebert
Linda M
LM
Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Canada S7N 5B4. linda.hiebert@usask.ca
Wice
Sandra M
SM
Ping
Tilly
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics*; D008297:Male; D010314:Partial Thromboplastin Time; D051381:Rats; D017208:Rats, Wistar; D000078222:Tinzaparin; D014018:Tissue Distribution
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin