Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to a...

Patient and graft survival following renal transplantation have improved markedly over the past decade, meaning that physician attention has turned more towards minimizing short- and long-term toxicities associated with immunosuppressive regimens. Gastrointestinal (GI) adverse events are common following renal transplantation and all immunosuppressive regimens have been associated with such events. Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) are potential components of immunosuppression regimens, and are associated with the most successful outcomes in kidney transplantation. The effects of MMF and EC-MPS are likely mediated via the active metabolite mycophenolic acid (MPA). The GI events caused by both MMF and EC-MPS may, in part, be related to MPA, independent of the formulation or route of administration. MPA may produce GI events either through direct action or through the action of it metabolites. However, many other factors may cause GI events observed following renal transplantation. These include the surgery itself and concurrent diseases such as diabetes, and bacterial, viral, fungal and parasitical infections. Additionally, numerous concomitant non-immunosuppressive agents, including antibiotics hypoglycaemic and proton-pump inhibitors, can be associated with GI events. In a recent trial in renal transplant patients with severe diarrhoea, approximately 50% of patients achieved resolution of diarrhoea through methods other than altering their immunosuppressive regimens. Indeed altering of the immunosuppressive regimen may lead to the risk of acute rejection. Thus, in order to reduce the risk of rejection and subsequent damage to the graft, it is important to consider other causes of GI events in renal transplant patients before altering immunosuppressive regimens

The pharmacokinetics of piceatannol, pinosylvin and rhapontigenin were characterized in male Sprague-Dawley rats after single intravenous doses of 10 mg kg−1 of each stilbene. Serial blood samples were collected via a catheter inserted into the right jugular vein and plasma samples were analysed for the selected stilbenes concentrations using reverse phase HPLC methods. After an acute intravenous dose of piceatannol, plasma AUC, urine t½, CL and Vd were 8.48 ± 2.48 μgh mL−1, 19.88 ± 5.66 h, 2.13 ± 0.92 Lh−1 kg−1 and 10.76 ± 2.88 Lkg−1 (mean ± s.e.m.), respectively. The acute intravenous dose of pinosylvin yielded the plasma AUC, urine t ½, CL and Vd values of 5.23 ± 1.20 μgh mL−1, 13.13 ± 2.05 h, 1.84 ± 0.44 Lh−1 kg−1 and 2.29 ± 0.56 Lkg−1 (mean ± s.e.m.), respectively. Rhapontigenin intravenous dosing yielded the plasma AUC, urine t½, CL and Vd values of 8.39 ±0.10 μgh mL−1, 25.31 ± 1.46 h, 1.18 ± 0.035 Lh−1 kg−1 and 11.05 ± 0.17 Lkg−1 (mean ± s.e.m.), respectively. Each stilbene was extensively glucuronidated. These stilbenes were predominantly eliminated via non-urinary routes. All three stilbenes were highly distributed into tissues and were highly extracted by the liver. The detectable plasma half-lives of these xenobiotics appear to be relatively short. However, utilizing urinary concentration-time data, much longer elimination half-lives were evident. The estimates of oral bioavailability characterize these stilbenes as poorly bioavailable compounds.