Probenecid serum concentrations

Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins. Additional pharmacokinetic information can be found in Table 45.1. 

Although the terminal half-life of cidofovir is about 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17-65 hours, thus allowing widely spaced administration. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Peak serum concentrations when administered with probenecid (see Clinical Uses) are about 19 g/mL. Cerebrospinal fluid penetration is poor after intravenous administration. Elimination involves active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. 

Penicillins and Probenecid. A number of organic acids are actively transported from the blood into the tubular urine and vice versa. In some situations, these agents interfere with each other s excretion. Probenecid (e.g., Benemid) can increase the serum concentrations and increase and prolong the activity of penicillin derivatives by blocking their tubular secretion. This is an interaction that has been used to therapeutic advantage in the treatment of certain infections. 

Probenecid increases the serum concentrations of cinox-acin (145), enoxacin (146), and nalidixic acid (147) probably by inhibiting their renal tubular secretion. 

Probenecid can increase the serum concentration of rifampicin this can reduce costs and hepatotoxicity in long-term therapy (124). Interactions of rifampicin with probenecid have been reviewed (105). 

Zidovudine is rapidly absorbed from the G1 tract with peak serum concentrations occurring within 30 to 90 minutes. It binds to plasma proteins to the extent of 35 to 40%. Zidovudine is rapidly metabolized in the liver to the inactive 3 -azido-3 -deoxy-5 -0-beta-D-glucopyranuronosylthymi-dine (GAZT), which has an apparent elimination half-life of 1 hour. Zidovudine undergoes glomerular filtration and active tubular secretion. Coadministration of zidovudine with agents such as dapsone, pentamidine, amphotericin B, flucytosine, vincristine, vinblastine, adriamycin, and interferon with potential to cause nephrotoxicity or cytotoxicity to hematopoietic elements, enhance its risk of adverse effects. Probenecid will inhibit the renal excretion of zidovudine. 

Spina SP, Dillon EC. Effect of chronic probenecid therapy on cefazolin serum concentrations. Ann Pharmacother (2003) 37,621-4. 

Kampffmeyer HG, Hartmann I, Metz H, Breault GO, Ske HR, Till AE, Weidner L. Serum concentrations of ampicillin and probenecid and ampicUlin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356). EurJCtin Pharmacol (1975) 9, 125-9. 

Cornelius CE, Schroeter AL, Lester A, Martin JE. Variations in serum concentrations of penicillin after injections of aqueous procaine penicillin G with and without oral probenecid. Br J VenerDis (1971) 47, 359 3. 

The mean 12-hour urinary recovery of norfloxacin 200 mg was reduced by about half in 5 subjects vflienthey were given probenecid 1 g. Norfloxacin serum concentrations were unaffected. ... 

Comparing the area under the curve for intramuscular administration and intravenous administration indicated that the bioavailability of the intramuscularly administered piperacillin was 70-80%. Urinary recovery after 24 hr was 60%. Oral administration of probenecid (1 g) 1 hr prior to the intramuscular injection of 1 g of piperacillin resulted in enhanced mean peak serum concentrations, an increased area under the curve, and a lengthened half-life. The volume of distribution, as well as the clearance rate, was also decreased. This is further evidence that a significant component of the urinary excretion is due to tubular secretion. Animal pharmacology has indicated varying degrees of elimination of piperacillin in the bile. 

Burch et al. (1979) reported that mean peak serum concentrations of 49 xg/ml were achieved 1 hr after intramuscular administration of 1 g of ceforanide to patients with normal renal function. Twelve hours after the 1-g dose, serum concentrations of 4.7 jxg/ml were still present. Smyth et al. (1979) studied the human pharmacokinetics of ceforanide in normal subjects (Table VIII). The plasma half-life of ceforanide was 2.8 hr. [The extended half-life possibly results from the presence of the 3 -carboxy-methyltetrazole side chain (Section II,B,2,d).] Urinary recovery in subjects receiving from 2 to 4 g intravenously was 92%, with the majority of the dose being excreted in the first 6 hr. Jovanovich et al. (1980) found that the serum concentrations, serum half-life, and urinary recovery were all unaffected by concomitant administration of ceforanide (intramuscularly) and probenecid (orally). This suggests that the renal elim-... 

Luthy et al. (1979) studied the pharmacokinetics of cefotaxime in healthy human volunteers. Doses of 0.5, 1, and 2 g of cefotaxime were administered by intravenous infusion over 15 min. Concentrations of cefotaxime in the serum measured just after the end of the infusion were 41, 93, and 160 p.g/ml, respectively. With increasing doses, serum concentrations rose in a nonlinear fashion as the result of a decrease in total body clearance. Renal clearance of cefotaxime modestly exceeded the creatinine clearance rate, which suggests some tubular secretion. This was confirmed in studies using probenecid (Bax et al., 1980). The mean plasma half-life was 1.25 hr. Sixty percent of the administered dose was excreted in the urine. Protein binding was 30% (Neu et al., 1979a). 

Ceftazidime was dosed intramuscularly and intravenously to human volunteers (Table XII). Peak serum concentrations of 10, 23, and 27 p,g/ ml were obtained after intramuscular doses of 0.25, 0.5, and 0.75 g. The plasma half-life varied from 1.4 hr for the low dose to 1.8 hr for the high dose. Serum concentrations of 8 p,g/ml were still present 1.5 (0.25 g dose), 4.2 (0.5 g dose), and 6.1 hr (0.75 g dose) after intramuscular administration. Urinary recovery of ceftazidime varied from 48 to 88% in 88% in humans. Serum levels of 61 fig/ml were measured immediately after intravenous administration of 0.5 g of ceftazidime to human volunteers. Preliminary experiments indicated that concomitant administration of probenecid had no effect on the rate of excretion of ceftazidime. This indicates that ceftazidime is excreted by glomerular filtration and not by tubular secretion. 

The absorption and excretion of carbenicillin in man has been reported [396]. The antibiotic is not absorbed intact from the gut intramuscular injection (which is painful) often provides adequate serum levels (approximately 20 Mg/ntl) but infections with Pseudomonas strains having minimum inhibitory concentrations up to, or higher than, 100 Mg/ml require intravenous thbrapy to achieve such levels. No evidence of active metabolite formation has been obtained. Marked reductions in the half-life (and serum levels) of carbenicillin follow extracorporeal dialysis or peritoneal dialysis, the former producing the most striking effect [397]. These results were, of course, obtained in patients with severe renal failure. Patients with normal renal function rapidly eliminate the drug but, as with all penicillins, renal tubular secretion can be retarded by concurrent administration of probenecid. 

Serum uric acid concentrations continue the probenecid dose that maintains normal concentrations... 

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

Aherne, G.W., Piall, E., Marks, V. et al. (1978) Prolongation and enhancement of serum methotrexate concentrations by probenecid. British Medical Journal, 1, 1097-1099. 

Reduction of the serum urate concentration can be accomplished pharmacologically by increasing the renal excretion of uric acid or by decreasing its synthesis. The drugs used most widely to increase uric acid excretion are probenecid and sulfinpyrazone. Several other uricosuric drugs are available in Europe, but they have not been approved for use in the United States. 

The symptoms of acute gout respond to anli-innammatory drugs suchasindomelh-acin. but it should be noted that these drugs have no direct effect on the serum urate level. Low-dose aspirin should be avoided as it inhibits renal urate excretion. Treatment must also be directed at the hyperuricaemia. Drugs such as probenecid which promote urate excretion can be used prophylactically. A diet which is low in purines and alcohol may be prescribed in an effort to reduce the plasma urate concentration. Allopurinol, a specific inhibitor of the enzyme xanthine oxidase which catalyzes the oxidation... 

Mechanism Uricosuric agents (probenecid, sulfinpyrazone) are weak acids that compete with uric acid for reabsorption by the weak acid transport mechanism in the S2 segment of the proximal renal tubule. At low doses, these agents may also compete with uric acid for secretion by the tubule and (occasionally) can even elevate serum uric acid concentration. Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid) over much of its dose range. 

Bint AJ, Reeves DS, Holt HA. Effect of probenecid on serum cefoxitin concentrations. J Antimicrob Chemother (1977) 3, 627-8. 

Shanson DC, McNabb R, Haj ipieris P. The effect of probenecid on serum araojq cillin concentrations up to 18 hours after a single 3 g oral dose of amojq ciUin possible implications for preventing endocarditis. J Antimicrob Chemother (1984) 13,629-32. 

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