Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys -Intravenous Bolus Studies

Abstract

14 bolus studies with probenecid in a dose range of 8.2–164 mg/kg were carried out in 3 monkeys. The protein binding of probenecid in the plasma was studied by an ultra-centrifugation method. Plasma clearances of both total and unbound probenecid decreased with increasing doses, while the volume of distribution and fraction of metabolites excreted in the urine remained constant. The urinary excretion rates of probenecid and its metabolites were measured in a bladder-catheterized monkey and were found to be urine flow dependent. Since the rate-limiting step for the excretion of the metabolites did not depend on the formation rate only, biliary recycling was speculated.

Probenecid: Its Chromatographic Determination, Plasma Protein Binding, and in vivo Pharmacokinetics in Dogs

“…4), a two-compartment open model rather than other models best fitted the PK of probenecid in normal dogs. A non-linear PK of probenecid was reported at an intravenous dose of 1,000 mg in monkeys [3]. In our study, it was not clear if non-linear PK observed at an intravenous bolus dose of 20 mg/kg in dogs, since the injected dose might be too low to saturate high-affinity plasma protein binding of probenecid, as indicated in Figs.…”

“…1) compared with the other methods reported [2,3,5,8,9,11]. The analytical method entailed a simple and the much better procedure; i.e., HCl and methanol to be added to plasma samples and centrifuged, and it was not necessary to dry out the samples as reported previously [5,8,9].…”

“…Moreover, it was calculated that at a concentration about 210 μg/ml in plasma, the high-and low-affinity binding becomes equal (34%) and total binding ratio is 68%. Chiang and Benet [3] reported probenecid binds from 89-73% over a concentration range of 40-800 μg/ml in humans. Similar observation in humans has been reported by Dayton et al [5] and Emanuelsson et al [6].…”

Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys – Infusion Studies

“…I] have been re ported to be dose-dependent in humans over the dose range of 0.5-2 g [1][2][3] and in dogs over the range of 40-160 mg/kg [4]. Our pre vious intravenous bolus studies in monkeys also indicated that the plasma clearance of probenecid was dose-dependent over the dose range of 8-160 mg/kg [5], However, probenecid metabolites: the glucuronide con jugate of probenecid (II), the 2-hydroxy me tabolite [p-(N-2-hydroxypropyl-N-propylsulfamoyl)-benzoic acid. III], the 3-hydroxy metabolite [p-(N-3-hydroxypropyl-N-propylsulfamoylj-benzoic acid, IV], the N-depropyl metabolite [p-(N-propylsulfamoyl)-benzoic acid, V] and the carboxy metabolite [p-(N -2-carboxyethyl -N -propylsulfamoyl) -benzoic acid.…”

“…2 restrained rhesus monkeys, monkey C weighing 7.9 and monkey D weighing 8.6 kg, with permanent catheters in the iliac vein and artery were prepared as in the previous studies [5] Plasma and urine samples o f 0.1-1 ml were as sayed for probenecid and its metabolites III and V by a gas-liquid chromatographic method as described in our previous publication [5].…”