Determination of renal tissue ibandronate levels in rats with normal and mildly impaired renal function

BackgroundAfter entering the blood, bisphosphonates are immediately bound to bone or excreted unchanged by the kidney. During renal excretion about 0.5% of administrated dosage remains in kidney tissue. The renal tissue level of bisphosphonates (RTL) decreases over time and remains at about 0.15% after 3 weeks, but the influence of renal insufficiency (RI) is unclear.MethodWe investigated the influence of mild to moderate RI on RTL of ibandronate (IBD). First a method for determination of RTL was implemented and validated. We measured RTL in rats with normal renal function (SHAM) and after unilateral nephrectomy (UNX). In each case one SHAM and one UNX groups received one or alternatively 9 times every 3 weeks a dosage of 1.5 mg/kg IBD. After the last dosage the rats were sacrificed and RTL of IBD were determined.ResultsIn SHAM-rats IBD concentrations increased from 272.7 ng/g kidney after one injection to 428.9 ng/g kidney after nine injections (p < 0.0001). RTL in UNX rats likewise increased significantly (p < 0.0001) from 289.9 ng/g kidney to 520.2 ng/g kidney.ConclusionOur study found a 1.6 fold increase of RTL in SHAM rats and a 1.8 fold increase of RTL in UNX rats after nine versus one injection. As steady state is generally reached after five half-lives we anticipate no further accumulation on continued treatment.