The pharmacokinetics of azithromycin, a new azalide antibiotic, were examined in man. Approximately 37% of a single oral dose of 500 mg was bioavailable and produced a peak serum concentration of 0.4 mg/l. Multiple dose regimens (two doses of 500 mg separated by 12 h and followed by 500 mg qds for five days, or two doses of 250 mg separated by 12 h and followed by 250 mg qds for nine days) produced only slight increases in peak serum concentrations. The serum protein binding of azithromycin declined from about 50% at 0.02 mg/l to 12% at 0.5 mg/l. Tissue concentrations of azithromycin were much higher than serum concentrations. After two 250 mg doses 12 h apart, peak azithromycin concentrations exceeded 3 mg/kg in prostate, tonsil and many other tissues. Concentrations in tissues declined with apparent half-lives of 2.3 days in prostate and 3.2 days in tonsil. The high tissue concentrations suggest that proposed standard dosage regimens of 500 mg qds on day 1 followed by 250 mg qds for four days, or three daily dosages of 500 mg, will produce tissue concentrations above 3 mg/kg in a variety of tissues. Since these tissue concentrations exceed the MICs of relevant pathogens, these dosage regimens should be effective against respiratory tract and soft-tissue infections. A single 1 g dose may be effective in the treatment of many sexually transmitted diseases.

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Sulbactam, a new beta-lactamase inhibitor, has pharmacokinetic characteristics in humans similar to those of ampicillin and amoxicillin. Its half-life in humans is approximately 1 h. In a two-compartment pharmacokinetic model, the apparent volume of distribution for the central compartment is approximately 12 liters, and half of the dose is found in the central compartment in the postdistributive phase. Approximately 75% of a parenteral dose is excreted unchanged in urine. The coadministration of sulbactam with ampicillin, penicillin G, or cefoperazone has essentially no effect upon the kinetics of either the beta-lactam antibiotic or sulbactam.

The unique pharmacokinetics of azithromycin are characterized by high, sustained tissue concentrations. The concentrations of azithromycin were predicted, following various multiple dose regimens, from concentrations in tonsillar, prostatic, and uterine tissues following single oral doses. Following a five-day treatment regimen (500 mg on day 1, followed by 250 mg on days 2-5), or a three-day regimen (500 mg daily for three days), concentrations of azithromycin in tonsillar tissue, representative of respiratory tract tissues, will continuously be greater than the MICs for key target pathogens (Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus) in infections of the respiratory tract for up to 10 days. Since tissue concentrations above the MICs for infecting organisms were correlated with efficacy in animal models of infection, short treatment regimens consisting of once-daily oral administration of azithromycin should be effective in the treatment of a variety of infections. A single 1 g oral dose will provide concentrations in the uterus and prostate, representing urogenital tissues, above the MIC for Chlamydia trachomatis for approximately 10 days. Thus, this regimen should be effective in the treatment of chlamydial infections of the genital tract.

Trovafloxacin (CP-99,219) is a new fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria. The pharmacokinetics and safety of trovafloxacin were characterised in healthy male volunteers after administration of single oral doses of 30, 100, 300, 600 and 1000 mg. trovafloxacin was rapidly absorbed and serum concentrations reached a maximum approximately 1 h after dosing. The corresponding mean Cmax values (mean +/- SD) were 0.3 +/- 0.0, 1.5 +/- 0.5, 4.4 +/- 1.1, 6.6 +/- 1.4 and 10.1 +/- 0.5 mg/L. Terminal-phase half-life was independent of dose, with an overall mean of 9.9 +/- 2.5 h. Generally, Cmax and AUC0-infinity increased linearly with dose. Less than 10% of the administered dose was recovered unchanged in urine. Over the dosing range, trovafloxacin renal clearance was fairly constant, averaging 0.67 +/- 0.36 L/h. Trovafloxacin binding to serum proteins was moderate (70%). Trovafloxacin was well tolerated at doses of 300 mg or below. There were no significant changes in the clinical chemistry or haematology parameters evaluated over the entire dosing range.

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.

Aims To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine. Methods The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo‐controlled, open, randomized, four‐way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC‐ECD. Results Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min−1 kg−1, juice vs 6.93 ml min−1 kg−1, water; Vdss 22.7 l kg−1, juice vs 21.0 l kg−1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(–) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0.957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control. Conclusions Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 g/ml after a 4-g dose) and the area under the concentration-time curve (82 g ⅐ h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.