Metabolism of pindolol in patients with renal failure

Abstract

Increased metabolism of pindolol in renal impairment has previously been suggested by pharmacokinetic calculations. The present study was a pharmacokinetic and metabolic investigation in 7 patients with severe renal impairment (endogeneous creatinine clearance below 5 ml/min). All the patients received pindolol 5 mg t.d.s. 5 days. On the sixth day, after an overnight fast, 14C-pindolol 5 mg was given orally as a solution to drink. Blood samples were taken for up to 72 h and urine was collected at intervals up to 96 h for measurement of unchanged pindolol by a fluorimetric method and total radioactivity by liquid scintillation counting. Metabolites in blood and urine were analysed after separation by HPLC. It was found that the plasma levels following a single dose of 14C-pindolol were similar to those observed in healthy volunteers, but the elimination half-life was slightly increased u tp 11.5 h. The observed steady state plasma concentrations of pindolol were twice as high but they are still in the therapeutic range of 10 to 100 ng/ml. Therefore, the dose of pindolol could have been reduced by a factor 2, but the reduction was not essential. No active metabolite of pindolol was found in plasma or urine, but elimination of the metabolites was decreased. The elimination half-life following multiple doses was prolonged compared to normal and it was quite comparable to that found fort pharmacodynamic half-life in renal patients. The discrepancy between the present findings and the previous results for metabolism and pharmacodynamic half-life was probably due to the sensitivity of the fluorimetric assay of pindolol.

Kidney Transplantation Down-Regulates Expression of Organic Cation Transporters, Which Translocate β-Blockers and Fluoroquinolones

“…However, these values can change according to the therapeutic protocol and in pathological conditions: for example, the AUC for atenolol in patients with terminal renal failure increases to 500 μM·h . Down-regulation of OCT in renal failure, as experimentally demonstrated here and elsewhere, ,, may be the reason for increased steady state plasma concentrations and/or elimination half-life observed for atenolol, pindolol, and ofloxacin in patients with renal disease.…”

Stereoselective renal clearance of pindolol in humans.

“…If metabolism in the kidney were an important route of elimination, one might expect that the metabolic clearance of pindolol would be impaired in the diseased kidneys. In patients with liver disease, a substantial decrease in the clearance of racemic pindolol has been observed, which suggests that the metabolism of pindolol is occurring to a large extent in the liver (15,16 Another mechanism that may have been responsible for the stereoselective renal clearance of pindolol is stereoselective renal transport. In agreement with other studies (12,17), we observed that the renal clearance of unbound pindolol was greater than the GFR, which indicates that pindolol is actively secreted by the kidneys.…”

Enantioselectivity in the steady‐state pharmacokinetics and transplacental distribution of pindolol at delivery in pregnancy‐induced hypertension

“…13 Pindolol metabolites excreted in urine are mainly glucuronides, hydroxy-glucuronides, or hydroxysulphates, products which are dependent on the activity of UDP-glucuronosyltransferases, cytochrome P-450 system, or arylsulfatases. 9,19 Hormonal factors play an important role in the regulation of glucuronidation activity. 20 The increased clearance of oxazepam and paracetamol in pregnant women, as well as of paracetamol, temazepam, and clofibric acid in patients treated with oral steroid contraceptives, demonstrates the influence of sex-related factors on the glucuronidation-dependent elimination of drugs.…”

“…7 Pindolol is cleared approximately equally by both metabolism and renal excretion. 6,[8][9][10] The renal clearance of racemic pindolol exceeds the glomerular filtration rate, indicating that the drug is actively secreted. 8,11 Hsyu and Giacomini 8 reported that the renal elimination of pindolol is stereoselective in healthy subjects.…”