Pharmacokinetics of minoxidil in patients with cirrhosis and healthy volunteers.

OBJECTIVES: To determine the effect of reduced hepatic function on the pharmacokinetics of minoxidil. The pharmacokinetics of antipyrine, lorazepam, and indocyanine green were included as indicators of hepatic function. METHODS: Eight mild cirrhotics and eight healthy subjects received antipyrine (po), lorazepam (IV), indocyanine green (IV) and minoxidil 5 mg (po). Blood and urine were sampled for up to 72 h after each drug, and drug concentrations were measured by validated HPLC methods. Blood pressure and heart rate were measured for safety. RESULTS: For unchanged minoxidil, the serum elimination rate constant was significantly smaller and mean residence time was significantly longer in cirrhotic patients. Urinary elimination rate constant for minoxidil glucuronide was significantly smaller and fraction of dose excreted in urine was significantly higher in cirrhotic patients. Antipyrine elimination was significantly slower for cirrhotic patients. No differences were observed in lorazepam pharmacokinetic parameters. CONCLUSION: Pharmacokinetic analysis suggests a longer dosage interval may be appropriate in patients with hepatic impairment. In the absence of multiple-dose minoxidil pharmacodynamic studies in this population, minoxidil should be used as in other populations: begin with a modest dose, and adjust the dose based on clinical response.

Pharmacokinetic comparison of flurbiprofen in end-stage renal disease subjects and subjects with normal renal function.

This study compared the pharmacokinetics of flurbiprofen (F) and three major metabolites in patients with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) with the pharmacokinetics of F in normal subjects. A single 100-mg dose of F was administered to each of nine normal subjects and eight ESRD subjects. Blood and urine samples were collected in both groups; serial and end of dwell dialysate samples were obtained from the ESRD subjects. Plasma was analyzed for both the R and S optical isomers of F and its major metabolite, 4'-hydroxy-flurbiprofen (HF). Urine and dialysate were analyzed for F and three known metabolites. Plasma concentrations of F in the ESRD subjects were approximately 50% of the values obtained from the normal subjects (P less than .05). Flurbiprofen half-life and Tmax were not different. Elimination of HF was reduced in ESRD subjects. Urinary data suggest that HF was the major metabolite excreted (36% of the dose) in normal subjects whereas 3',4'-dihydroxy-flurbiprofen was the major metabolite (9% of the dose) excreted in the ESRD group. Mean urinary recovery of the dose was 73% in the normal subjects, but only 16% in ESRD subjects. Neither F nor its metabolites were detected in dialysate. Small enantiomer differences were seen. This study suggests that ESRD subjects have lower plasma levels of F than normal subjects when administered equal size doses. Accumulation of metabolites may occur in ESRD subjects upon multiple dosing. Enantiomer differences are not clinically significant.

Binding of pyrimethamine to human plasma proteins and erythrocytes.

A high-performance liquid chromatographic (HPLC) assay was developed for pyrimethamine in plasma, red blood cells (RBCs), and buffer for the purpose of studying its plasma protein binding and RBC partitioning. Pyrimethamine (1000 ng/ml) was 94% bound to plasma proteins on average, depending on the pH of plasma. A comparison of the lower and upper range of plasma concentrations that would be achieved after a malaria prophylaxis dosing regimen (25 mg/week) showed that the fraction unbound was significantly lower at 120 ng/ml than at the upper plasma concentration of 360 ng/ml, 3.5 vs 4.9%, respectively. Nonlinear regression of the effect of albumin concentration (g/L) on plasma binding yielded the equation: fraction unbound = 1/[(0.421 * albumin concentration) + 1] (R2 = 0.99). There was no binding to normal levels of alpha 1-acid glycoprotein (AAG). The mean ratio of the concentration of pyrimethamine in RBCs to that in plasma (RBC:plasma ratio) was 0.42, while the mean RBC:buffer ratio was 5.2. Binding to hemolysate did not account for all of the RBC uptake, suggesting that binding to or partitioning into RBC membranes may be important. Because pyrimethamine binding depends on both albumin concentration and pyrimethamine concentration in the plasma, these studies predict greater free fractions of pyrimethamine associated with the higher doses given for toxoplasmosis (75 mg/day) and with the hypoalbuminemia associated with AIDS and malaria.

Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers.

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.

Comparative pharmacokinetics of azlocillin and piperacillin in normal adults.

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.

Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses.

The pharmacokinetics and safety of orally administered ciprofloxacin (Bay o 9867) were examined in 12 healthy male volunteers who received sequential doses of 250, 500, 750, and 1,000 mg. The individual and mean data were best described by biexponential disposition and elimination, assuming an apparent zero-order rate of absorption. The peak serum concentrations determined from the individual data occurred at approximately 1.5 h after each dose and ranged from 0.42 to 4.2 micrograms/ml; the mean peak concentrations increased in proportion to the dose. The areas under the curve determined from the mean data were also proportional with respect to dose. The mean elimination half-lives calculated from pooled data were 4.1, 4.1, 6.9, and 6.3 h for doses of 250, 500, 750, and 1,000 mg, respectively. Longer half-lives but proportional area-under-the-curve values after the 750- and 1,000-mg doses implied that smaller fractions of ciprofloxacin were absorbed after these doses, although nonlinear kinetics could not be ruled out. The mean serum concentrations 12 and 24 h following each dose were greater than or equal to 0.08 and 0.01 micrograms/ml, respectively. The urinary concentrations ranged from 30 to 500 micrograms/ml for at least 12 h after administration and were greater than or equal to 9 micrograms/ml at 24 h following each dose. The urinary recovery level of unchanged ciprofloxacin over a 24-h period ranged from 28 to 44%. The mean renal clearances for each dose ranged from 300 to 500 ml/min. Ciprofloxacin was well tolerated, and no significant clinical or laboratory abnormalities were observed.

Single-dose model for predicting steady-state valproic acid serum concentrations in seizure patients.

Valproic acid serum concentrations predicted by a single-dose prediction model were compared with steady-state serum concentrations measured after the start of therapy in seizure patients. Ten patients receiving valproic acid for the first time or who had not been taking the drug for two or more weeks were entered into the study. The patients' therapies were initiated with the prescribed doses of valproic acid and then maintained on fixed doses and dosing intervals until steady-state trough serum samples were obtained. Initial 5-ml blood samples were collected six to 14 hours after the ingestion of the first dose; a 5-ml steady-state trough sample was drawn in the same manner three to seven days later. Both free and total drug concentrations were determined within 48 hours of sample collection using gas-liquid chromatography. The elimination rate constant was estimated from age-specific population half-life values found in the literature. Six patients (five children, aged four to 16 years) and one adult (aged 87 years) completed the study. There was a statistically significant correlation between predicted and measured steady-state valproic acid serum concentrations for both free and total concentrations. The single-dose prediction model accurately predicted steady-state valproic acid serum concentrations in these seizure patients.

Salicylate removal during plasma exchange in normal volunteers.

The removal of salicylate by plasma exchange in normal subjects was studied. Six healthy men volunteers were given aspirin 975 mg every six hours for five days before undergoing plasma exchange. Blood samples for determination of serum salicylate concentrations were obtained from each subject before the 0730 aspirin dose on study days 3-6 and at hourly intervals for several hours before and after plasma exchange, which was performed at approximately 1500 on study day 5. Blood cell counts, serum albumin concentrations, and other blood chemistry values were also evaluated. Salicylate concentrations in serum and in plasma removed by exchange were determined spectrophotometrically. In each subject, serum salicylate concentrations before and after plasma exchange were compared, as were total area under the serum concentration-time curve and salicylate clearance on and off plasma exchange. The mean trough salicylate concentration at 1930 after plasma exchange on day 5 was significantly lower than the mean trough concentration at 1330 before plasma exchange on the same day. The mean AUC during the six-hour period in which plasma exchange occurred was significantly smaller than the AUC in the six-hour period before plasma exchange. Serum albumin concentrations decreased by a mean of 1.7 g/dl as a result of plasma exchange; however, the mean +/- S.D. amount of salicylate removed was only 191.0 +/- 52.4 mg. The amount of salicylate removed by plasma exchange in this study does not appear to be clinically important.(ABSTRACT TRUNCATED AT 250 WORDS)

Clodronate kinetics and bioavailability.

Carbon 13-labeled clodronate disodium was given to healthy adult men by intravenous infusion and orally in a crossover design. Serum and urine levels were determined as a function of time by isotope-ratio mass spectrometry. Clodronate disodium (Cl2/MDP) is primarily excreted unchanged by the kidney; more than 80% of the intravenous dose was recovered within 48 hr. The serum concentrations-time curve over the first 8 hr after intravenous dosing appears biexponential with the disposition phase having a harmonic mean half-life (t 1/2) of 2 hr. The mean serum clearance was found to be 1.4 ml min-1 kg-1 and the apparent volume of distribution was approximately 25% of body weight. Simulations and computer fitting of the cumulative urinary excretion and urinary excretion rates based on the biexponential serum decay curve demonstrated the presence of a slow disposition component with a t 1/2 of 12.8 hr. Thus, the disposition kinetics of Cl2MDP appear to be triexponentials, although the slowest component is not of major significance after a single dose and could not be verified because of a lack of serum data after 8 hr. Cl2MDP is poorly absorbed with an absolute bioavailability of only 1% to 2%.

Pharmacokinetics of saccharin in the rat. Renal clearance in vivo and in the isolated perfused kidney.

Saccharin is not metabolized and is rapidly eliminated in urine of the rat. Factors that affect renal excretion, i.e., protein binding, glomerular filtration rate (GFR), and tubular secretion, would thus be important in determining saccharin clearance. The renal clearance of saccharin in the ureter-cannulated rat and in the isolated perfused rat kidney (IPK) were studies after the administration of saccharin in doses of 0.02, 1, or 100 mg/kg. Binding of saccharin in rat plasma and perfusate was variable and insensitive to changes in concentration. The mean free fraction was approximately 0.70 in rat plasma and 0.40 in perfusate. Renal clearances were relatively constant, with a mean of 2.2 ml/min in vivo and 1.9 ml/min in the IPK. Saccharin clearance was consistently higher than the GFR, supporting involvement of tubular secretion in the renal elimination of saccharin. Correlation of data from IPK experiments with the data from in vivo experiments substantiate the utility of this preparation for studying the renal excretion of drugs.

Single-dose fasting bioequivalence assessment of erythromycin stearate tablets in man.

The bioequivalence of film-coated erythromycin stearate tablets produced by five different manufacturers was evaluated in a balanced incomplete block design involving the five formulations given to 30 fasted subjects over a 3-week study period. Serum levels of erythromycin activity were determined microbiologically. Statistical analysis of variance was performed on the observed bioavailability parameters: maximum serum concentration (Cmax), time to maximum serum concentration (Tmax), and area under the serum concentration-time curve (AUC). There was no statistical difference between formulations for the Tmax parameter. Formulation differences were found, however, based on the analysis of variance of the Cmax and AUC parameters. Two products, although not significantly different from one another, showed significantly greater Cmax and AUC values than the other three products.