The influence of various test meals and fluid volumes on the relative bioavailability of commercial formulations of doxycycline hyclate and tetracycline hydrochloride was studied in healthy human volunteers. Serum levels of tetracycline were uniformly reduced by approximately 50% by all test meals, whereas serum levels of doxycycline were reduced by 20%. The reduction of tetracycline serum levels will likely be of clinical significance. The bioavailability of each drug was almost identical from an oral solution and from capsules in fasted subjects. The rate of doxycycline absorption was reduced when capsules were administered with a small volume of water, but the overall efficiency of absorption of both drugs was essentially independent of co-administered fluid volume. The use of 8-h serum data provides a reliable estimate of drug bioavailability for tetracycline and, to a lesser extent, for doxycycline.Although the tetracycline antibiotics may be bactericidal to some microorganisms at high concentrations, their activity is primarily bacteriostatic (14). It is therefore important that circulating levels of these compounds be maintained above the minimum inhibitory concentration (MIC) for pathogenic organisms during a course of treatment. In view of this, there has been considerable interest in factors influencing the absorption of tetracyclines after oral doses and the degree to which these factors affect circulating levels of antibiotic.Inhibition of absorption of the tetracyclines due to chelation by heavy-metal ions is extensively documented (8,12,16,20,21). Inhibition by antacid preparations is also well established. The latter effect appears to be due to a combined influence of heavy-metal ion chelation and also a decreased dissolution rate of tetracycline (2) or the dosage form in which it is contained (9). Milk and other dairy products inhibit the absorption of tetracyclines to varying degrees. Rosenblatt and associates (22) reported that doxycycline absorption was reduced by about 20% in the presence of skimmed milk, whereas the absorption of demethylchlortetracycline was reduced by about 70%. Mattila and associates (18) reported 50 to 60% reduction in bioavailability of tetracycline, oxytetracycline, and methacycline in the presence of whole milk whereas the absorption of doxycycline was not significantly affected. Interactions influencing the absorption of tetracyclines have recently been reviewed (19).In view of the above, and also the superior tissue distribution (5, 10) and apparently longer biological half-life of doxycycline (11,22), this lipid-soluble compound appears to have several advantages over other tetracyclines. From the results obtained with dairy products and also specific heavy metals, it is generally considered that food has less influence on the absorption of doxycycline than that of other tetracyclines. In this study, the influence of solid test meals and fluid volumes on the bioavailability of doxycycline and tetracycline was examined in healthy human volunteers under controlled co...

The pharmacokinetics of the new aminoglycoside antibiotic netilmicin were examined after single intravenous injections at two different dose levels to elderly male patients. The drug obeyed two-compartment model kinetics in serum, and elimination was monoexponential from 1 to 2 h after dosing. Netilmicin levels in serum were above minimum inhibitory concentration values for most susceptible organisms for up to 8 h after dosing in normal individuals and for at least 12 h in uremic patients. Urine levels of netilmicin were uniformly above minimum inhibitory concentration values throughout 24 h after dosing. Netilmicin distribution characteristics were largely independent of both dose level and renal function. Netilmicin elimination kinetics were independent of dose level but were markedly influenced by renal function. Relationships are described between netilmicin elimination and renal function indicators, which provide a basis for dosage adjustment in individuals with renal function impairment.Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside which is effective against gram-negative bacteria, including strains resistant to gentamicin, sisomicin, and tobramycin (5,6,9).In a previous study at this institution, netilmicin was shown to be clinically effective and free from toxic side effects when given intramuscularly to elderly male patients at doses of 1.0 to 2.5 mg/kg every 8 h for 7 days (A. Baumueller and P. 0. Madsen, submitted for publication). A preliminary study in a similar patient population showed that after rapid intravenous irjection, netilmicin had a serum halflife of about 4.5 h, and the half-life was linearly related to serum creatinine (Baumueller and Madsen, submitted for publication).Here we report on the pharmacokinetics of netilmicin after single intravenous doses to elderly male patients with normal and impaired renal function. MATERIALS AND METHODSSubjects and protocols. Subjects were 42 patients in the urology ward of the Veterans Administration Hospital, Madison, Wis. Details of subjects' ages, weights, creatinine clearances, and serum creatinine values are described in Table 1. Almost all of the patients were suffering from lower urinary tract obstruction, infections associated with lower urinary tract obstruction, urethral stricture, carcinoma or hyperplasia of the prostate, or bladder tumor. Some patients had indwelling bladder catheters; most of them were not bedridden during the study.For analysis, patients were divided into three groups based on creatinine clearances. Groups 1, 2 and 3 had creatinine clearances greater than 100 ml/ min, between 50 and 100 ml/min, and less than 50 ml/min, respectively. Creatinine clearances were obtained from 12-h urine collections, except in the case of some severely uremic patients where 24-h urine clearances were obtained. Patients received netilmicin by rapid intravenous injection into a forearm vein at dose levels of 1 or 2 mg/kg. The injection was administered in 5 ml of physiological saline, and the injection time was 2 m...