Probenecid and penicillins

Probenecid is well tolerated. Approximately 2% of patients develop mild GI irritation. The risk is increased at higher doses, and caution should be used in those with a history of peptic ulcer. It is ineffective in patients with renal insufficiency and should be avoided in those with creatinine clearance of <50 mUmin. Mild hypersensitivity reactions may occur in 2—4% of patients serious hypersensitivity is extremely rare. The appearance of a rash during the concurrent administration of probenecid and penicillin G presents the physician with an awkward diagnostic dilemma. Substantial overdosage with probenecid results in CNS stimulation, convulsions, and death from respiratoryfailure. 

Severe drug-drug interactions are known to occur between methotrexate and NSAIDs, probenecid, and penicillin G partially due to inhibition of renal... 

OAT-mediated secretion of methotrexate. By using mouse proximal tubule cells stably expressing human transporters, methotrexate has been demonstrated to be taken up via hOAT3 and hOATl at the basolateral side of the proximal tubule and effluxed or taken up at the apical side via hOAT4, where drug interactions occur between methotrexate and NSAIDs, probenecid, and penicillin G (Takeda et al., 2002). 

Salicylates, sulfonamides, probenecid, and high dose penicillin may... 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

Figure 2.19. Active secretion of organic acids in the proximal tubule, a Secretion of p-Aminohippnrate. Two exchange transporters are involved. The first one is located in the basolateral membrane its operation is electrically driven. Transport by the second one, which is located in the apical (luminal) membrane, is drivenby concentrationgradients. This transporter is inhibited by probenecid, b Penicillin G, like p-aminohippurate, is a substrate for both transporters. Probenicid inhibits the apical transporter and therefore prevents the rapid elimination of penicillin.

Interference with active transport. Organic acids are passed from the blood into the urine by active transport across the renal tubular epithelium. Penicillin is mostly excreted in this way. Probenecid, an organic acid that competes successfully with penicillin for this transport system, may be used to prolong the action of penicillin when repeated administration is impracticable, e.g. in sexually transmitted diseases, where compliance is notoriously poor. Interference with renal excretion of methotrexate by aspirin, of zidovudine by probenecid and of digoxin by quinidine, contribute to the potentially harmful interactions with these combinations. 

Probenecid and Gout. The story of the discovery of probenecid and its usefulness in the treatment of gout is well known to medicinal chemists. Certain sulfanilamide compounds were observed to decrease the renal clearance of penicillin in a study aimed primarily at increasing the usefulness of penicillin during those days when this antibiotic was difficult and expensive to make. 

Many means for prolonging the sojourn of the antibiotic in the body and thereby reducing the frequency of injections have been explored. Probenecid blocks renal tubular secretion of penicilhn, but it is used rarely for this purpose. More commonly, repository preparations of penicillin G are employed. The two such compounds currently favored are penicillin G procaine (WyciUin, others) and penicillin G benzathine (BiciUin L-A, Permapen). Such agents release penicillin G slowly from the area in which they are injected... 

In 1950 (but not reported until 1975) a woman with subacute bacterial endocarditis was given probenecid orally and penicillin by intravenous drip, which was kept open with minimal doses of heparin. After a total of about 20 000 units of heparin had been given over a 3-week period, increasing epistaxes developed and the clotting time was found to be 24 minutes (normal 5 to 6 minutes). This was controlled with protamine. However, no reports of this interaction appear to have been made subsequently. This interaction seems unlikely to be of general significance. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

In those with gout, the serum uric acid level is usually elevated. Sulfinpyrazone increases the excretion of uric acid by the kidneys, which lowers serum uric acid levels and consequently retards the deposit of urate crystals in the joints. Probenecid (Benemid) works in the same manner and may be given alone or with colchicine as combination therapy when there are frequent, recurrent attacks of gout. Probenecid also has been used to prolong the plasma levels of the penicillins and cephalosporins. 

Penicillins and cephalosporins Probenecid, aspirin Blocked excretion of /3-lactams Use if prolonged high concentration of /J-lactam desirable... 

Aqueous procaine penicillin G 2.4 million units IM daily plus probenecid 500 mg orally four times daily, both for 10-14 days 6 Aqueous crystalline penicillin G 50,000 units/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days or... 

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. 

Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin eUmination ... 

Penicillin or cephalosporin therapy The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about the normal rate when dosage of probenecid is adequate. 

Probenecid also inhibits the tubular secretion of most penicillins and cephalosporins and usually increases plasma levels by any route the antibiotic is given. Pharmacokinetics Probenecid is well absorbed after oral administration and produces peak plasma concentrations in 2 to 4 hours. It is highly protein bound (85% to 95%). Probenecid is excreted in the urine primarily as metabolites. 

Excretion - Penicillins are excreted largely unchanged in the urine by glomerular filtration and active tubular secretion. Nonrenal elimination includes hepatic inactivation and excretion in bile this is only a minor route for all penicillins except nafcillin and oxacillin. Excretion by renal tubular secretion can be delayed by coadministration of probenecid. Elimination half-life of most penicillins is short (no... 

Drugs that may affect penicillins include allopurinol, aminoglycosides (parenteral), aspirin, beta blockers, chloramphenicol, erythromycin, ethacrynic acid, furosemide, indomethacin, phenylbutazone, probenecid, sulfonamides, tetracycline, and thiazide diuretics. Drugs that may be affected by penicillins include aminoglycosides (parenteral), anticoagulants, beta blockers, chloramphenicol, cyclosporine, oral contraceptives, erythromycin, heparin, and vecuronium. 

Action Monobactam, -1- cell wall S5mth Dose Adul. 1—2 g IV/EM q6-12h Peds. Premature 30 mg/kg/dose IV ql2h Term children 30 mg/kg/dose q6-8h X in renal impair Caution [B, +] Disp Inj SE NA /D, rash, pain at inj site Interac tions T Effects W/probenecid, aminoglycosides, i-lactam antibiotics X effects W7 cefoxitin, chloramphenicol, imipenem EMS Monitor for S/Sxs of super Infxn may cause aUCTgic Rxns rare cross-sensitivity Rxns to penicillins and cephalosporins have been rqwrted OD May cause Szs symptomatic and supportive... 

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