Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.     

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.     

Clinical evaluation of cefixime in children

A new beta-lactamase-stable oral cephem antibiotic, cefixime (CFIX), was evaluated for safety, efficacy and pharmacokinetics in children. CFIX was effective in 19 of 20 cases (95%) with bacterial infections. The drug was especially effective against the cases of pneumonia due to beta-lactamase-producing H. influenzae or B. catarrhalis. Pharmacokinetic parameters of CFIX (3 mg/kg) with premeal administration were as follows: Kel 0.328 +/- 0.066 hr-1, T 1/2 2.14 +/- 0.36 hrs, AUC 10.9 +/- 8.7 micrograms X hr/ml, and Vd/F 1.64 +/- 1.42 L/kg. In most of the cases tested, the urinary excretion rate in 12 hours was 5 to 17%. A dose of 3 mg/kg twice daily seems to be adequate for a regular treatment.     

Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias

A new antiarrhythmic agent, 1-(2,6- dimethylphenoxy )-2-aminopropane (mexiletine), was investigated in 10 patients with chronic premature ventricular contractions (PVCs) to evaluate the antiarrhythmic efficacy and the pharmacokinetics after single intravenous, single oral and repeated oral dosings of mexiletine 150 mg. Mexiletine was well absorbed from the intestinal tract. The relative bioavailability was 83.2 +/- 8.9% (mean +/- S.E.). The time-concentration curve of mexiletine fitted in well with two-compartment open model. Elimination half-life, volume of distribution and plasma clearance were 10.54 +/- 0.26 h, 2.10 +/- 0.49 l/kg, 6.01 +/- 0.63 ml/min/kg, respectively. The computer-simulated time-concentration curves of multiple oral dosings , which were based on the kinetic parameters from single oral dosing, conformed well with measured concentrations. This might be applied to predict the plasma level of mexiletine. The steady state of plasma mexiletine level was reached 4-5 days after 450 mg/day dosings and ranged 0.75-2.18 micrograms/ml. In 6 of 10 patients, the frequency of PVCs was suppressed more than 75% as compared with the pre-medication value. Mexiletine was well tolerated at a dose of 450 mg/day. However, of 4 patients with the dose increased to 600 mg/day, the administration was ceased in three patients due to gastrointestinal symptoms and tremor. All of these adverse reactions disappeared when the administration was stopped. These results suggest that mexiletine is effective against ventricular arrhythmias and the dosage should be carefully adjusted. The prediction of plasma level would be applied to the dosage regimen of mexiletine.     

Comparative pharmacokinetics of caffeine in young and elderly men

The pharmacokinetic behavior of caffeine was compared in a group of eight healthy young men aged 20.5 +/- 2.0 years (mean +/- SD), and in a group of eight healthy, elderly men aged 71.2 +/- 3.9 years. Each subject was given a 5 mg/kg dose of caffeine as either an aqueous oral solution or an intravenous infusion over 30 min using a randomized crossover design. Plasma and urine samples were collected for 24 hr following each dose and analyzed for caffeine content using high-performance liquid chromatography. The peak times (tmax), peak concentrations (Cmax), and the percentage of the peroral dose systemically available, F(%), were essentially identical in both age groups, indicating that caffeine was absorbed rapidly and completely after peroral administration. These results also indicated that the first-pass metabolism observed in rats following the peroral administration of caffeine does not occur in either human group studied here. The elimination of caffeine during its terminal disposition phase was log-linear. Several between-group comparisons of other pharmacokinetic parameters were made. Although the average elimination rate constant was greater in the elderly, the difference did not reach statistical significance, possibly because of the considerable intersubject variability in the elimination rate of caffeine, with half-lives ranging from 2.27 to 9.87 hr. The average apparent volume of distribution was significantly lower in the elderly subjects while the clearances were slightly, but not significantly, larger in the elderly subjects. It appears that most aspects of the pharmacokinetic behavior of caffeine are very similar in young and elderly men.     

Effects of age on the pharmacokinetics of mexiletine

Mexiletine (1-methyl-2-(2, 6-xylyloxy)ethylamine hydrochloride) is an antiarrhythmic drug eliminated primarily by hepatic metabolism. The influence of age on the plasma pharmacokinetics of mexiletine was assessed in seven young and ten elderly healthy subjects. Mexiletine (50 mg) was administered orally three times daily for 10 days. The use of low doses of mexiletine was possible owing to the development of a new fluorescence high performance liquid chromatography method with a limit of sensitivity lower than 20 ng/ml. No differences in the pharmacokinetic parameters of mexiletine related to age were observed. At steady-state plasma concentrations were 0.121 +/- 0.033 microgram-ml in the young volunteers, and 0.135 +/- 0.150 microgram/ml in the older subjects. The elimination t 1/2 was 11.4 +/- 1.78 h in the young subjects and 10.48 +/- 3.06 h in the elderly. The data provide no justification for lowering the recommended dose of mexiletine for older patients.     

Pharmacokinetics of mexiletine and its metabolites, hydroxymethylmexiletine and p-hydroxymexiletine, after single oral administration in healthy subjects

Pharmacokinetics of mexiletine and its major metabolites, p-hydroxymexiletine and hydroxymethylmexiletine, were studied in 10 healthy subjects after administration of a single oral 400 mg dose. Mexiletine was extensively metabolized to hydroxymethylmexiletine and less to p-hydroxymexiletine. Mean metabolic ratio (Rm) was 0.54 and 0.18 respectively. Peak serum concentrations (Cmax) for mexiletine (0.686 +/- 0.110 micrograms/ml), hydroxymethylmexiletine (0.507 +/- 0.087 micrograms/ml), and p-hydroxymexiletine (0.096 +/- 0.046 micrograms/ml) occurred after 3.0, 4.0 and 4.2 +/- 0.6 h. Disposition parameters for mexiletine were as follows: volume of distribution (V lambda), 5.44 +/- 1.44 l/kg; serum clearance (CL) 8.08 +/- 1.23 ml/min/kg. There were no significant differences in elimination half-life (t1/2) and mean residence time (MRT) for mexiletine and its metabolites. Double-peak phenomenon was observed for all the subjects on elimination phase of mexiletine, hydroxymethylmexiletine and p-hydroxymexiletine.     

The disposition of recainam hydrochloride during and after intravenous loading and maintenance infusion in cardiac patients

Recainam hydrochloride is a newly synthesized propylurea compound demonstrating potent antidysrhythmic effects. Recainam was administered as a loading dose of 3 mg/kg/40 minutes followed by a continuous infusion of 0.9 mg/kg/hr for 23 hours and 20 minutes to ten patients with cardiac disease and frequent PVCs (more than 30/hr). A total of 15 plasma samples were drawn over 36 hours during and after the infusion. Plasma recainam concentration was determined by high performance liquid chromatography (HPLC). The mean (+/- SD) postload and 24-hour plasma concentrations were 5.19 +/- 0.51 and 3.41 +/- 0.71 micrograms/mL, respectively. The data were best described by a two-compartment model yielding the following mean (+/- SD) pharmacokinetic parameters: lambda 1 = 2.62 +/- 0.68 hr-1, lambda 2 = 0.144 +/- 0.014 hr-1, t1/2 lambda 2 = 4.84 +/- 0.46 hr, CLT = 0.268 +/- 0.057 L/hr/kg, CLR = 0.143 +/- 0.052 L/kg/hr, CLNR = 0.125 +/- 0.041 L/hr/kg, Vdss = 1.3 +/- 0.19 L/kg, and Vd lambda 2 = 1.9 +/- 0.43 L/kg. There were no adverse reactions. Based on these data, recainam can be safely administered as a loading dose followed by a continuous infusion in patients with stable cardiac disease without significant ventricular dysfunction.     

Naltrexone disposition in man after subcutaneous administration

The metabolism, excretion, and pharmacokinetics of [15,16-3H2]naltrexone were studied in six human males after sc administration of the hydrochloride salt. Biological fluids were analyzed by a combination of high performance liquid chromatography with liquid scintillation measurement of radioactivity. After administration, naltrexone was rapidly absorbed into the systemic circulation. The mean absorption rate constant was 0.091 +/- 0.008 min-1 (half-life of 7.6 min). In general the metabolic, excretory, and pharmacokinetic patterns for naltrexone were similar to those observed after iv administration of naltrexone to man. The terminal phase plasma rate constant was 0.413 +/- 0.035 hr-1 (half-life of 1.68 hr) for parent drug and 0.0786 +/- 0.0090 hr-1 (half-life of 8.8 hr) for the major metabolite, 6 beta-naltrexone. An average of 76 +/- 6% (+/- SD) of the total radioactivity was recovered in the urine within 72 hr after administration. Naltrexone was found in the urine in both the free (3.4 +/- 0.8% of dose) and conjugated (6.8 +/- 2.1% of dose) form. 6 beta-Naltrexol was present in urine largely in the unconjugated form (28 +/- 7% of dose) but the conjugated form was also found (12 +/- 3% of dose).     

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.     

Influence of a single dose of ethanol on the kinetics of valproic acid in rats

A study was made of the influence of ethanol on the kinetics of valproic acid (VPA) in rats that received single doses of both compounds. Three groups of animals received a single dose of VPA (100 mg/kg) through a gastric tube, alone (Group I: controls) or together with ethanol at doses of 2.5 mg/kg (Group IIa) and 5 mg/kg (Group IIb). VPA was determined using the homogeneous immunoassay EMIT. VPA kinetics were fitted to an open two-compartment model with a first order two phase absorption process defined by the constants Ka1 and Ka2, where Ka1 would reflect the rate of gastric emptying, and Ka2 could express the true absorption constant. The groups of animals receiving ethanol showed a statistically significant decrease (p less than 0.05) in plasma concentrations of VPA compared with the control group. Ka2 increased in groups IIa and IIb compared with the control group (35.79 hr-1 and 36.61 hr-1 vs. 28.18 hr-1). However, Ka1 decreased in group IIb as compared with the control rats (2.34 hr-1 vs. 4.18 hr-1), whereas no modifications were seen in group IIa (4.35 hr-1). The t1/2 beta was greater in groups IIa and IIb than in the controls (8.77 hr and 7.78 hr vs. 4.55 hr), and Ke was lower in those groups than in the controls (0.86 hr-1 and 0.48 hr-1 vs. 0.98 hr-1), suggesting a decrease in the elimination of VPA following administration of a single dose of ethanol.     

Disposition and antiarrhythmic effect of lorcainide.

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.     

Comparison of pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly and young subjects.

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.     

Metabolic fate of carteolol hydrochloride (OPC-1085), a new beta-adrenergic blocking agent. (6) Pharmacokinetics of carteolol in the rat, dog, rabbit and man]

The kinetics (absorption, distribution and excretion) of carteolol were investigated after oral and intravenous administration to man, rats, Beagle dogs and rabbits. The half-life of carteolol in plasma was 1.22 approximately 1.45 hr in rats, 1.73 approximately 2.08 hr in dogs and 1.42 approximately 1.43 hr in rabbits, and was independent of the route of administration. The absorption rate constants, obtained from log(C1-C) approximately time plot, after oral administration were 1.89 hr-1 in rats, 1.04 hr-1 in dogs and 1.54 hr-1 in rabbits. There were no differences between tablet and film coated tablet in the pharmacokinetic parameters of carteolol in man after oral 30 mg (tablet or film coated tablet) administration [half life (t1/2)=4.50 hr (tablet), 4.30 hr (film coated tablet), elimination rate constant (k2) equals 0.154 hr-1 (tablet), 0.161 hr-1 (film coated tablet)]. The elimination rate constant, obtained from Sigma-minus plot after 2, 5 and 10 mg oral administration, was 0.137 approximately 0.160 hr-1.     

Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers--10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6--received a single 200 mg oral dose of racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily). Serial blood and urine samples were collected and pharmacokinetic parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73.4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine.     

Pharmacokinetics of valproic acid in the elderly

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.     

The effect of antacid and ranitidine on droxicam pharmacokinetics.

Droxicam is a nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of concomitant administration of antacid or ranitidine on droxicam pharmacokinetics has been investigated. On three separate phases, 15 healthy volunteers received a single oral 20-mg dose of droxicam either alone, with antacid (400 mg aluminum hydroxide + 400 mg magnesium hydroxide, three times/day), or with ranitidine (300 mg, two times/day) for 6 days. Piroxicam, the active substance from droxicam, was quantified by high-performance liquid chromatography. The pharmacokinetic parameters for droxicam given alone were: maximum peak plasma concentration (Cmax) = 1.53 +/- .21 micrograms/mL (mean +/- SD), time to peak concentration (Tmax) = 7.5 +/- 2.1 hr, t1/2a = 1.38 +/- .82 hour, t1/2el = 53.3 +/- 11.9 hr, Cl/F = 2.98 +/- .71 mL/min, volume of distribution (Vd/F) = 13.2 +/- 1.8 L and area under the curve (AUC) = 117.6 +/- 26.8 micrograms/hour/mL. The subject effect was significant for all the pharmacokinetic parameters except for the absorption half-life (P < .05). Concomitant antacid or ranitidine administration had no significant effect on any of the droxicam pharmacokinetic parameters. The results of this study suggest that antacid or ranitidine do not significantly alter the oral absorption or pharmacokinetic disposition of single-dose droxicam.     

N-acetylprocainamide kinetics during intravenous infusions and subsequent oral doses in patients with coronary artery disease and ventricular arrhythmias

The kinetics of N-acetylprocainamide (NAPA) were studied in 5 patients (all men, mean age = 62) with coronary artery disease and ventricular arrhythmias during loading infusions of 0.22-0.45 mg/kg/min, prolonged (19-48 hrs) intravenous infusions 2.5-5.2 mg/min, and in 4 of the patients, during subsequent oral doses 1.5-3 g every 8 hrs. Serum, concentrations of NAPA were determined by high-performance liquid chromatography. The individual concentration-time profiles could, with one exception, be described by a two-compartment, open, kinetic model with apparent first-order elimination. The kinetic variables were: initial distribution volume (Vc) 0.20 +/- 0.11 l/kg (mean +/- SD); steady-state distribution volume (Vss) 1.58 +/- 0.55 l/kg; distributional clearance (Cle) 133 +/- 23 ml/(kg X hr); absorption rate constant (Ka) 0.354 +/- 0.173 hr-1; and fraction of dose reaching systemic circulation (F) 1.00 +/- 0.14. The data for one patient who had received increasing oral dosages of 1.5, 2, 2.5 and 3 g every 8 hours resulted in systematic underprediction of observed concentrations at the two highest oral dosing rates. This suggests the possibility of some degree of nonlinearity or time-dependent change in the kinetic behavior of NAPA. Only low concentrations of procainamide, less than 1 mg/L, were found at the end of the infusions.     

Pharmacokinetic properties of mezlocillin in ambulatory elderly subjects

Twelve healthy ambulatory elderly subjects (mean age, 73-78 years) randomly received either a 4-g or 5-g dose of mezlocillin intravenously. One week later the regimen was repeated and patients crossed over to the other dose. Peak serum concentrations were 165 mg/L and 281 mg/L for the 4-g and 5-g doses, respectively. For both doses, differences in t1/2 beta (1.32 hr vs 1.13 hr), AUC (275 mg.hr/L vs 403 mg.hr/L), CL (207 mL/min vs 174 mL/min), CLR (59 mL/min vs 45 mL/min), CLNR (152 mL/min vs 130 mL/min) were not statistically significant. The differences in Varea (22.4L vs 168.8L, P less than or equal to .01) and Cmax (216.6 mg/L vs 317 mg/L, P less than or equal to .05) were statistically significant. Comparison with pharmacokinetic parameters obtained in younger subjects following the 5-g dose reveals that in the elderly the AUC, Varea, and CLNR are higher whereas the CL and CLR are lower. The elderly demonstrated an increase in nonrenal clearance compared with young subjects that is not fully compensatory. The increased AUC in the elderly group suggests that clinical studies examining mezlocillin doses and dose intervals in the treatment of serious infections are warranted in infected elderly patients.