Pharmacokinetics of imipenem and cilastatin in volunteers.

Imipenem/cilastatin sodium consists of imipenem, a broad-spectrum carbapenem antimicrobial agent, and cilastatin sodium, an inhibitor of dehydropeptidase I, the renal enzyme that catalyzes the metabolism of imipenem. When imipenem is administered alone by the intravenous route, the levels excreted in the urine are low and variable (6%-38% of the dose) between subjects. Kinetics of imipenem in plasma are less variable, and the half-life of imipenem in plasma is 1 hr. When imipenem is coadministered with an equal amount of cilastatin, the amount of imipenem excreted in the urine represents 70% of the plasma clearance and the plasma half-life remains at 1 hr. Whether administered alone or with imipenem, the urinary excretion of cilastatin is 70%-80% of the dose administered, and its plasma half-life is also 1 hr. Thus, the pharmacokinetics of both agents are linear across the therapeutic dose range, and no accumulation of these agents occurs for therapeutic regimens. Decreases in renal function slow the elimination of both compounds and require a reduction in dosage when the glomerular filtration rate is less than 30 ml/min per 1.73 m2.

Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans.

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of N-formimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of N-formimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH.

Urinary recovery of N-formimidoyl thienamycin (MK0787) as affected by coadministration of N-formimidoyl thienamycin dehydropeptidase inhibitors.

N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an N-formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N-formimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.

Effect of antacids on the bioavailability of diflunisal in the fasting and postprandial states.

Diflunisal is long-acting salicylate derivative. We examined the effect of single concomitant doses of three antacids on diflunisal bioavailability under fasting or fed conditions (30 min after finishing a standard meal). With the use of an open, randomized, and balanced design, one 250-mg diflunisal tablet was given to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area uiven to each of 12 healthy men under six conditions: fasted, no antacid; fed, no antacid; fasted, 15 ml of aluminum hydroxide gel; fed, 15 ml of aluminum hydroxide gel; fasted, 10 ml magnesium hydroxide suspension; and fed, 15 ml of an aluminum hydroxide/magnesium hydroxide mixture. Diflunisal plasma 0- to 48-hr area under the time curve (AUC), peak plasma concentrations, and 0-to 96-hr urinary excretion were determined. Food (alone) decreased peak plasma concentrations by 16% (P less than 0.05) but did not affect AUC or urinary excretion. Under fasting conditions, aluminum hydroxide reduced AUC by 26% (P less than 0.01), peak plasma concentrations by 46% (P less than 0.01), and urinary excretion by 14% (P less than 0.05). Magenisuum hydroxide suspension (in the fasting state) increased the early plasma concentrations (by 130% at 0.5 hr and 64% at 1 hr, P less than 0.05) and increased AUC by 10% (P less than 0.05) but had no effect on urinary excretion. In the fed state neither aluminum hydroxide nor the aluminum hydroxide/magnesium hydroxide mixture had any detectable effect.

Uricosuric properties of diflunisal in man.

1 The uricosuric effect of diflunisal was studied in eleven normal subjects. 2 Urine and serum uric acid levels were measured and used to assess the effect. 3 Diflunisal caused statistically significant decreases in serum uric acid levels and increases in uric acid clearance at 250 and 375 mg twice daily. 4 Diflunisal taken on an empty stomach caused epigastric discomfort in the high dose group which was obviated when the drug was taken with meals. 5 Diflunisal caused no abnormalities in the measured haematological, urological or biochemical parameters.

An overview of nonsteroidal antiinflammatory agents (NSAIA).

Since the rediscovery of willow bark extract (salicin) in 1763, there has been a continuing effort to improve efficacy and reduce the side effects of antiinflammatory agents through chemical modification and innovation. The second-generation NSAIA's, phenylbutazone and indomethacin, provided clear support for the idea that these objectives were obtainable. The success of steroid programs in enhancing potency and modifying side effects, coupled with the development of effective screening techniques for identifying antiinflammatory activity, stimulated an enormous effort to develop new NSAIA's. The products of this effort are now coming to the clinic. Although less successful than the steroid program in enhancing potency, the effort has succeeded in changing and reducing side effects. As a result, the clinician has a greater choice of agents for dealing with individual patient variability and achieving greater patient acceptance.