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Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi of [(14)C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.

Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.

Cefamandole nafate (CM) and cephalothin sodium (CP) were administered as prophylaxis in a randomized, prospective study to 30 consecutive patients undergoing prosthetic cardiac valve insertion. A single dose of 20 mg/kg was given intramuscularly during anesthesia induction, and serial plasma antibiotic concentrations, atrial muscle and cardiac valve tissue antibiotic levels, plasma bactericidal activity against pathogenic staphylococci, and infectious complications were determined and compared for the two drugs. Both antibiotics produced high plasma levels (>20 μg/ml 30 min after injection) which fell less than 25% during the period of cardiopulmonary bypass. However, CM levels were significantly higher at most time periods (P<0.05) than CP levels. CP levels were undetectable in atrial muscle from 14 of 15 patients and in valves from 10 of 15 patients. In contrast, CM bioactivity was found in all tissues. Differences in tissue antibiotic concentration could not be accounted for by differences in plasma concentrations or by CP tissue binding and were assumed to be caused by differences in penetration. Plasma bactericidal activity against staphylococci was equal for the two drugs (median titer, 1:16). No infections were seen in either group. CM appeared to be an effective and perhaps preferable prophylactic antibiotic for use during cardiac surgery.

The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its major metabolite, paraxanthine, was investigated in healthy volunteers. Ten xanthine-free, fasting males were given 100 mg of caffeine orally 24 h before being given ciprofloxacin and again with the third dose of ciprofloxacin (750 mg administered every 12 h). Blood samples were serially collected after both doses of caffeine and after the first and last doses of ciprofloxacin. Ciprofloxacin significantly increased the half-life of caffeine (from 5.2 +/- 1.2 to 8.2 +/- 2.5 h) and the area under the caffeine concentration-time curve (from 16.3 +/- 6.6 to 25.9 +/- 7.8 micrograms.h/ml) while decreasing the total body clearance (from 106 +/- 41.6 to 58.2 +/- 28.8 ml/min per 1.73 m2). In addition, the rate of conversion of caffeine to paraxanthine was significantly delayed. There was no significant linear correlation between the urinary recovery of oxociprofloxacin at 0 to 12 h and the change in the area under the caffeine concentration-time curve. There was also a small but statistically significant increase in the area under the ciprofloxacin concentration-time curve during simultaneous administration of caffeine. We concluded that ciprofloxacin causes a significant increase in the half-life of caffeine and in the area under the caffeine concentration-time curve by reducing total body clearance. This interaction is due at least in part to a delay in the conversion of caffeine to paraxanthine. The clinical significance of these observations remains to be determined. Lastly, caffeine may alter the kinetics of ciprofloxacin, a possibility which should be more fully explored.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

Mezlocillin was previously reported to exhibit dose-dependent pharmacokinetics. These reports suggest that it may be possible to administer a relatively large dose at a longer interval than is usual and still achieve therapeutic concentrations in serum. In a randomized, crossover study, we compared concentrations of mezlocillin in serum after a single dose and at steady state in 12 healthy volunteers who received 4 g every 6 h and 5 g every 8 h. A slight, but statistically significant, dose-dependent effect was observed upon the area under the concentration-time curve and total body clearance. No accumulation was observed with either schedule. Although concentrations in serum were higher after the 5-g dose, the more frequent administration of the 4-g dose schedule produced serum concentrations above the MIC for susceptible bacteria for a greater portion of the day. In the absence of clear guidelines from human studies which relate serum concentrations to clinical response, the available data indicate that the more frequent dosage schedule is appropriate for severe infections.

The pharmacokinetics of cefmenoxime were determined after a 30-min intravenous infusion of 15 mg/kg of total body weight to 33 adult subjects with normal renal function (CLCR, greater than 80 ml/min per 1.73 m2, group I), mild renal insufficiency (CLCR, 40 to 79 ml/min per 1.73 m2, group II), moderate renal insufficiency (CLCR, 10 to 39 ml/min per 1.73 m2, group III), or severe renal impairment, (CLCR, less than 10 ml/min per 1.73 m2, group IV) or to patients between hemodialysis (CLCR, less than 10 ml/min per 1.73 m2, group V). Concentrations of cefmenoxime in serum and urine were determined by high-pressure liquid chromatography, and serum concentrations were fit to a two-compartment model. There was no significant relationship between creatinine clearance and either peak serum concentrations or volume of distribution at steady state. Patients in group I excreted 81% of the dose into the urine within 24 h; recovery decreased with worsening renal function. The mean terminal half-lives in groups I to V were 1.06, 1.50, 3.55, 4.60, and 11.4 h, respectively. There were good linear relationships between creatinine clearance, and the elimination rate and total body clearance of cefmenoxime. Dosage recommendations for subjects with renal insufficiency are proposed.

A high-performance liquid chromatographic method for the measurement of moxalactam concentrations in serum was modified to permit the simultaneous measurement of both moxalactam and cefazolin. We then studied whether the simultaneous administration of both moxalactam and cefazolin to normal subjects would produce profiles of serum concentration versus time which were the same as those obtained after the administration of each drug individually. Six healthy adults received a 30-min infusion of cefazolin (10 mg/kg), followed in 2 days by the same dose of moxalactam. After 2 days, both antibiotics were administered together. A two-compartment model was found to adequately characterize the data, and the serum concentration curve for each drug when given alone was statistically identical to that obtained after simultaneous administration. Cefazolin was found to produce a significantly greater peak serum concentration (105 +/- 14 versus 81 +/- 21 microgram/ml) and a significantly greater area under the curve (218 +/- 42 versus 157 +/- 19 . microgram h/ml). The terminal half-life of moxalactam was not significantly longer than for cefazolin (2.2 +/- 0.6 versus 2.0 +/- 0.6 h, respectively). The method of simultaneous administration may have distinct advantages over conventional methods for studies of comparative tissue penetration.