The influence of age and gender on the pharmacokinetics of moxifloxacin.

OBJECTIVE: Moxifloxacin is a new 8-methoxyfluoroquinolone with a broad antibacterial spectrum. The purpose of the present study was to determine the effects of age and gender on pharmacokinetics, surrogate pharmacodynamics, safety and tolerability of a single dose of moxifloxacin. DESIGN: This was a randomised, double-blind, placebo-controlled, parallel-group single dose trial in young and elderly healthy volunteers. PATIENTS AND PARTICIPANTS: The study included 36 volunteers in 3 age and gender groups: young males (mean age 32 years), elderly males (mean age 74 years), and elderly females (mean age 74 years). METHODS: Participants received either a single 200mg oral dose of moxifloxacin (8/group) or placebo (4/group). Blood samples for moxifloxacin pharmacokinetics were obtained before and up to 48 hours after administration. Urine samples were collected for pharmacokinetics, and volunteers were monitored for clinical adverse events and laboratory abnormalities. RESULTS: Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher in elderly females than in elderly males; however, when normalised for bodyweight, these pharmacokinetic parameters were not significantly different between the groups. Moreover, the plasma pharmacokinetics in elderly males were not meaningfully different from those in young males. Elimination half-life averaged 12 to 13 hours for the 3 groups. Surrogate pharmacodynamic measures were derived using AUC/MIC (minimal inhibitory concentration) and Cmax/MIC ratios. These assessments indicated that, given the linear pharmacokinetics of moxifloxacin previously demonstrated, a dose of 400mg would produce mean Cmax/MIC values in the different subgroups ranging from 10.4 to 15.4 for an MIC of 0.25, and 20.8 to 30.8 for an MIC of 0.125. The corresponding ranges of projected AUC/MIC ratios would be 112 to 158 for an MIC of 0.25, and 224 to 314 for an MIC of 0.125. The accepted target values of AUC/MIC and Cmax/MIC for quinolones are 125 and 10, respectively. There were no serious adverse events or differences in adverse event profiles between the groups. CONCLUSIONS: Moxifloxacin does not exhibit age- or gender-dependent pharmacokinetics. Oral doses of 200 to 400mg yield effective antibacterial concentrations on the first day of administration.

Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults.

OBJECTIVE: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrandomized, non-blinded, 7-day, multiple-dose study. METHODS: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL(CR) >90 ml/min/1.73 m2, n = 9), or patients with either mild (CL(CR) 61 ml/min/1.73 m2 to < or =90 ml/min/1.73 m2, n = 9), moderate (CL(CR) 30 ml/min/1.73 m2 to < or =60 ml/ min/1.73 m2, n = 8), or severe (CL(CR) <30 ml/min/ 1.73 m2, but not on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration-time curve (AUC)0-24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. RESULTS: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 microg/h/l vs 19.2 microg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40-60% higher (30.8 microg/h/l and 29.0 microg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 microg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. CONCLUSION: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.

Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers.

The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0.2 mg on mean plasma digoxin levels and the effect of digoxin on the single-dose pharmacokinetics of cerivastatin were assessed in 20 healthy normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After a 2-day washout period, subjects were given a loading dose of digoxin 0.5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1-digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic variables for cerivastatin, including area under the curve (AUC(0-24)), peak concentration (C(max)), time to peak concentration (T(max)), and elimination half-life (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.

Effects of beano on the tolerability and pharmacodynamics of acarbose.

Acarbose is an alpha-glucosidase inhibitor approved for the treatment of type 2 diabetes mellitus. Acarbose inhibits carbohydrate digestion, allowing an excessive amount of undigested carbohydrate to reach the colon. Bacterial fermentation of the carbohydrate produces intestinal gas, which can cause flatulence and abdominal pain. Beano, an over-the-counter enzyme preparation (alpha-galactosidase), diminishes intestinal gas production by enhancing the breakdown of certain carbohydrates before they reach the lower intestine. This study was undertaken to investigate whether concomitant administration of Beano and acarbose could reduce the flatulence associated with acarbose and, if so, whether Beano would interfere with the effects of acarbose on postprandial serum glucose concentration. In this randomized, double-masked, placebo-controlled, three-period crossover study, 37 patients with type 2 diabetes mellitus received acarbose 100 mg, acarbose 100 mg plus Beano, or placebo. The study population consisted of 20 males and 17 females who ranged in age from 36 to 72 years (mean, 56 years) and in weight from 62 to 142 kg (mean, 92 kg). Each treatment period consisted of 3 days, during which both acarbose and Beano were given at the beginning of each of three meals. There was a 4-day washout interval between each treatment period. The frequency and severity of flatulence were measured using a score compiled from patient diaries. As an additional measure of intestinal gas production, breath hydrogen concentration was measured on day 3 of each treatment period. Postprandial serum glucose concentration was measured at predetermined times after each morning dose to assess pharmacodynamic activity. Patients who took Beano with acarbose had a significantly lower flatulence score than did those who took acarbose alone (0.79 vs 1.09). Consistent with this finding, breath hydrogen concentration was lower after administration of acarbose plus Beano than with acarbose alone (31.2 ppm vs 50.5 ppm). Beano had variable effects on the ability of acarbose to reduce the postprandial serum glucose concentration. Although postprandial serum glucose levels were higher in patients who received acarbose plus Beano than in those who received acarbose alone, both treatments (with or without Beano) resulted in postprandial serum glucose levels that were significantly lower than those seen with placebo. Therefore, although Beano appeared to diminish the activity of acarbose, postprandial serum glucose concentrations still decreased significantly in patients taking Beano with acarbose. Beano has been shown to alleviate the flatulence accompanying acarbose treatment, but it may also interfere with the glucose-lowering effect of acarbose.

Pharmacokinetic disposition of sequential intravenous/oral ciprofloxacin in pediatric cystic fibrosis patients with acute pulmonary exacerbation.

OBJECTIVE: Information about the pharmacokinetics of fluoroquinolone antibiotics in high risk children is scant. This study examined the disposition of sequentially administered intravenous and oral ciprofloxacin, as well as provided dosing recommendations, for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients. METHODS: After enrollment in a Food and Drug Administration approved protocol, the pharmacokinetic profiles of ciprofloxacin (CIP) administered to 18 children with cystic fibrosis (ages 5 to 17 years) were studied at steady state after sequentially administered intravenous (10 mg/kg every 8 h) and oral (20 mg/kg every 12 h) doses. All children enrolled met published criteria for exacerbation of Pseudomonas aeruginosa lung infection and received CIP intravenously (given as a 1-h infusion) followed by oral administration, each for a minimum of 3 days. All patients were at a mild to moderate stage in their disease with National Institutes of Health scores between 37 and 83. Blood samples were drawn at 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 (after both i.v. and oral dosing) and 12 h (oral only) after CIP administration. CIP serum concentrations were determined by high performance liquid chromatography. RESULTS: After oral CIP mean +/- SD peak serum concentrations and peak times were 3.7 +/- 1.4 mg/l and 2.5 +/- 1.8 h, respectively, compared with 5.0 +/- 1.5 mg/l and 1.0 +/- 0.3 h after completion of the i.v. infusion. Maximum concentrations, when normalized for dose, were 0.52 +/- 0.12 and 0.19 +/- 0.07 mg/l/kg after i.v. and oral dosing, respectively. The mean bioavailability of oral CIP for all patients was 76%; younger patients appeared to absorb oral CIP less than older subjects, 68% vs. 95%, respectively. For all patients elimination half-lives were 2.6 +/- 0.6 and 3.4 +/- 0.7 h after i.v. and oral administration, respectively, and did not differ by age. Total clearance after i.v. administration was 19.5 +/- 10.9 liters/h. No significant CIP-related adverse effects were noted. CONCLUSIONS: CIP doses of 30 mg/kg/day i.v. and 40 mg/kg/day orally must be administered to children with cystic fibrosis to achieve optimal therapeutic concentrations.

Ciprofloxacin pharmacokinetics in burn patients.

Many drugs exhibit altered pharmacokinetic parameters in burn patients. We prospectively evaluated the pharmacokinetics of ciprofloxacin in eight burn patients with active infections. Each patient received a 400-mg dose of ciprofloxacin intravenously (i.v.) every 8 h, with each dose infused over 1 h by using a rate control device. Blood samples for analysis of plasma ciprofloxacin concentrations, determined by high-performance liquid chromatography, were obtained immediately predose, at the end of the infusion, and 1, 2, 3, 4, 5, 6, and 7 h after the end of the infusion. Urine was collected from 0 to 2, 2 to 4, and 4 to 8 h following the same dose, and an aliquot was saved for determination of the ciprofloxacin concentration. Urine was also collected for 24 h prior to this dose for measurement of creatinine clearance (CLCR). Pharmacokinetic parameters were estimated by noncompartmental analysis. Mean maximum and minimum plasma ciprofloxacin concentrations were 4.2 +/- 1.1 and 0.70 +/- 0.55 microgram/ml, respectively. Mean values for clearance (CL), renal clearance (CLR), volume of distribution, terminal elimination rate constant, half-life (t1/2), and area under the concentration-time curve (AUC) were 29.1 +/- 17.5 liters/h, 13.5 +/- 10.1 liters/h, 1.75 +/- 0.41 liters/kg, 0.222 +/- 0.098 h-1, 4.5 +/- 3.9 h, and 20.7 +/- 16.6 micrograms.h/ml, respectively. CL was higher and t1/2 was shorter than noted in previous studies of acutely ill, hospitalized patients. A good correlation was noted between creatinine clearance CL(CR) and both total ciprofloxacin CL (r = 0.85) and CLR (r = 0.84). A moderate inverse correlation was noted between percent body surface area burned and total ciprofloxacin CL (r = -0.55). An AUC/MIC ratio above 125 SIT-1 (where SIT is serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in five of eight patients (63%) with a MIC of 0.25 microgram/ml. At a ciprofloxacin dosage of 400 mg i.v. every 12 h, an AUC/MIC ratio above 125 SIT-1 would have been achieved in only two of eight patients (25%). We conclude that ciprofloxacin CL is highly variable, but generally increased, in burn patients compared with that in acutely ill, general medical and surgical patients. Because of an increase in CL, a ciprofloxacin dosage of 400 mg i.v. every 8 h is more likely to produce the desired response in burn patients than the same dose given every 12 h.

Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin.

To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin.

LC separation and induced fluorometric detection of rivastatin in blood plasma.

An LC procedure suitable for quantitative analysis of pg ml-1 concentrations of the HMG-CoA reductase inhibitor rivastatin in blood plasma was developed. The procedure involves an extraction step, chromatography on an ODS column, and fluorometric detection of a post-column photolytic decomposition product that was isolated and identified. The achieved quantitation limit (25 pg ml-1) facilitated analysis of relatively low rivastatin concentrations in plasma that were observed after 100-300 micrograms oral doses of rivastatin. At 25 pg ml-1 concentration the RSD ranged from 3.6 to 13.5% and mean deviation from the nominal value was 8.0%; at 8 ng ml-1 the RSD range was 0.7-3.6% while the mean deviation was -1.8%. The concentrations obtained with the LC procedure were compared to the concentrations obtained with a specific but less sensitive capillary GC method and a radioimmunoassay (RIA) procedure. Concentrations obtained with the HPLC and GC procedures agreed within experimental error; the RIA concentrations were about 30% higher.

Effects of cardiopulmonary bypass surgery on intravenous ciprofloxacin disposition.

The pharmacokinetic parameters of intravenous ciprofloxacin were examined in five adult male patients on three separate occasions of open heart surgery: the 24 h before cardiopulmonary bypass (CPB) surgery, (PRE), during surgery (SURG), and 48 to 72 h after surgery (POST). Serial blood (n = 16), urine, and SURG tissue samples were collected after intravenous administration of a single 300-mg dose of ciprofloxacin during each study period. All samples were assayed for ciprofloxacin by a specific high-performance liquid chromatographic method. Serum ciprofloxacin concentrations remained constant or continued to decline during the course of CPB surgery. A significant (P < 0.05) decrease in total body clearance was observed during the SURG and POST phases (298 and 306 ml/min/1.73 m2, respectively) compared with that during the PRE phase (364 ml/min/1.73 m2). Renal clearances and elimination half-lives were similar during all three study phases. A nonsignificant decline occurred in the apparent volume of distribution, from mean values of 2.1 and 2.0 liters/kg during the PRE and POST phases, respectively, to 1.7 liters/kg during the SURG phase. The mediastinal fat tissue ciprofloxacin concentrations ranged from 0.45 to 2.89 micrograms/g. Overall, little significant difference was noted in the disposition of intravenous ciprofloxacin during CPB surgery compared with that before and after surgery.

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double-blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoldipine (core-coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoldipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose-normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P less than .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 +/- 3.47 (5 mg), 11.84 +/- 13.85 (10 mg), 11.48 +/- 7.49 (20 mg), and 10.36 +/- 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoldipine core-coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoldipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

Pharmacokinetic profiles of ciprofloxacin after single intravenous and oral doses.

Ciprofloxacin was administered to 12 healthy male volunteers at doses of 300 and 400 mg intravenously (i.v.) and 500 and 750 mg orally in a randomized, double-blind, single-dose, four-period crossover study. On each treatment day, each subject received both oral and i.v. formulations, one of which was a placebo. Blood and urine samples were obtained through 24 h postdose. By each dosing route, the pharmacokinetic profiles were dose proportional. The 400-mg i.v. dose was equivalent to the 500-mg oral dose with respect to the area under the concentration-time curve and was equivalent to the 750-mg oral dose with respect to the maximum concentration of ciprofloxacin in serum. The oral bioavailability was 78.0%. The steady-state volume of distribution averaged 178 liters, and the terminal half-life in serum after i.v. dosing was approximately 4.3 h. Renal clearance accounted for approximately 60% of total body clearance. No significant adverse events were associated with either route of administration.

Effects of aluminum hydroxide and calcium carbonate antacids on the bioavailability of ciprofloxacin.

This study was designed to determine the effects of an aluminum hydroxide antacid and a calcium carbonate antacid on the bioavailability of ciprofloxacin (Cipro). Cipro (750 mg) was administered orally to 12 healthy volunteers in a three-way randomized crossover design. The three treatments included Cipro alone, four 850-mg calcium carbonate tablets taken 5 min before Cipro, and three 600-mg aluminum hydroxide tablets taken 5 min before Cipro. The relative bioavailability of Cipro when given with calcium carbonate was approximately 60% of the control value. When Cipro was given with aluminum hydroxide, the relative bioavailability was approximately 15%. Urinary recovery of Cipro in the aluminum hydroxide treatment group was approximately one-fourth of that in the calcium carbonate group. Although calcium carbonate decreased absorption to a lesser extent than aluminum hydroxide, these data suggest that antacids containing either aluminum or calcium should not be given concomitantly with Cipro.

Craniofacial suture stenosis: morphologic effects.

Craniofacial anomalies, such as Apert's and Crouzon's syndromes, are presumed to be related to premature growth arrest of cranial base growth sites. However, premature growth arrest at cranial vault sutures in animals appears to play a causative role in the development of cranial deformities characteristic of single-suture, or simple, craniosynostosis in humans. To study the possible causative role of cranial vault and other (interface) suture stenoses on the development of craniofacial deformity, a vault suture and an interface suture between the cranial vault and facial skeleton were simultaneously immobilized. Thirty-one New Zealand White rabbits at 9 days of age underwent implantation of dental amalgam growth markers adjacent to cranial vault and facial sutures. In the experimental group (n = 15), methylcyanoacrylate adhesive was applied over the coronal (vault) and frontonasal (interface suture between vault and facial skeleton) sutures to immobilize them. The remaining 16 animals served as sham-treated controls. All animals underwent serial radiographic cephalometry to document growth effects in the cranial vault, cranial base, and facial skeleton. Application of adhesive resulted in statistically significant (p less than 0.05) reduction in growth at the coronal and frontonasal sutures. This was accompanied by an overall significant reduction in neurocranial vault length during the first 30 days of development.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding.

The bioavailability of ciprofloxacin after its administration through a nasogastric (NG) feeding tube was studied in six healthy volunteers. Each subject received, on separate occasions, an intact 750-mg ciprofloxacin tablet, a crushed tablet as a suspension through an NG tube, and a crushed tablet as a suspension through an NG tube while receiving enteral feeding. No statistically significant differences were observed in the area under the curve, maximum concentration in serum, and time to peak concentration among these three modes of administration. These findings suggest that ciprofloxacin is well absorbed after administration via an NG tube (compared with an orally administered intact tablet) even in the presence of enteral feeding.

The effect of cirrhosis on the steady-state pharmacokinetics of oral ciprofloxacin.

The pharmacokinetics of ciprofloxacin, a carboxyquinolone, was studied after oral administration of the drug to seven patients with biopsy-proved cirrhosis and to seven healthy volunteers. Serum concentrations of ciprofloxacin and its three metabolites--desethylene ciprofloxacin (M1), sulfociprofloxacin (M2), and oxociprofloxacin (M3)--were measured by an HPLC procedure. The pharmacokinetic parameters for ciprofloxacin were not significantly altered in cirrhotic patients. The elimination half-life (t 1/2) and the area under the serum concentration versus time curve (AUC) were, respectively, 3.71 hours and 16.18 microgram.ml-1.hr-1 in the normal subjects and 3.47 hours and 18.38 micrograms.ml-1.hr-1 in patients with cirrhosis. The formation of oxociprofloxacin was reduced by approximately one half in the cirrhotic subjects, as the Cmax was 0.29 micrograms/ml in normal subjects versus 0.14 micrograms/ml in cirrhotic patients and the mean AUC(0-t) was 1.54 micrograms.ml-1.hr-1 in normal subjects versus 0.70 micrograms.ml-1.hr-1 in cirrhotic patients. However, there appeared to be no significant difference between groups with respect to desethylene ciprofloxacin and sulfociprofloxacin. Therefore it appears from this study that no dosage adjustment is required in patients with hepatic cirrhosis.

The effects of age and race on nitrendipine pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of a single 20-mg dose of nitrendipine (NTP) were studied in four groups of subjects (n = 9 per group). Group 1 were young white normotensive males, Group 2 were elderly white hypertensive males, Group 3 were black hypertensive males aged 40-55 years, and Group 4 were white hypertensive males aged 40-55 years. All other medications were withdrawn prior to NTP dosing. NTP was given in the morning 1 h after breakfast. Plasma samples for NTP assay were collected at predetermined times up to 48 h after dosing. Blood pressure was monitored before dosing, and at 0.5, 1, 3, 5, 12, and 24 h postdose. Pharmacokinetic parameters were found to be dependent on age. The area under the curve for Groups 1, 2, 3, and 4 was 50.5 +/- 19.4, 186 +/- 120, 107 +/- 49, and 88 +/- 43 ng h/ml, respectively (p less than 0.05). Corresponding values of elimination half-life were 9.9 +/- 1.3, 20 +/- 6.5, 13.3 +/- 6.1, and 15.9 +/- 8.0 h (p less than 0.05). Both diastolic and systolic blood pressures were significantly reduced from the baseline value in Groups 2, 3, and 4, with diastolic pressure remaining significantly lower than baseline at 24 h postdose. Based on the increased plasma levels and slower elimination of NTP in the elderly, as well as the measured blood pressure lowering, once daily dosing of NTP may be appropriate in some patients.

Effects of competitive red blood cell binding and reduced hematocrit on the blood and plasma levels of [14C]Indapamide in the rat.

The effects of chlorthalidone and acetazolamide on the red blood cell binding of indapamide were investigated. Both drugs caused a substantial decrease in the amount of indapamide bound to the erythrocytes in vitro. This effect was demonstrated by a change in the indapamide blood/plasma ratio from approximately 6 in control samples, to a value of 1 when either of the displacing agents was added. Coadministration of acetazolamide with 14C-labeled indapamide to rats, resulted in a 5-fold drop in the blood levels of total radioactivity, relative to rats dosed with [14C]indapamide alone. Concomitantly, there was a 2-fold increase in the plasma levels of total radioactivity after acetazolamide coadministration. In rats whose hematocrits had been reduced by extensive bleeding, there were only minor alterations in the blood/plasma partitioning of [14C]indapamide. Thus, chlorthalidone and acetazolamide were able to displace indapamide from erythrocytes in vitro and in vivo, possibly by competition at a carbonic anhydrase binding site. The pharmacokinetics of drugs which are extensively bound to erythrocytes may be significantly altered by the presence of other agents capable of competitive binding.

Dose-dependent pharmacokinetics and hypnotic effects of sodium gamma-hydroxybutyrate in the rat.

The pharmacokinetics of sodium-gamma-hydroxybutyrate (NaGHB) have been examined as functions of dose and route of administration. The elimination of NaGHB appeared to be controlled by a capacity-limited process which can be described by Michaelis-Menten kinetics. Oral absorption of NaGHB appeared to be fairly extensive in the dose range studied (200-1600 mg/kg), but the peak drug plasma concentrations achieved after oral dosing were relatively low and insensitive to changes in the magnitude of the dose, explaining the lack of pharmacological activity, viz., hypnosis, after oral NaGHB administration even at comparatively high doses. Plasma and brain concentrations were determined at the time when the animals recovered from the hypnotic effects of NaGHB. These concentrations also appeared to be dose-dependent, although the ratio of "waking" plasma to brain concentration was constant with respect to dose.