Cefodizime penetration into skin suction blister fluid following a single intravenous dose

Summary Cefodizime pharmacokinetics was investigated, evaluating drug concentrations in serum, skin suction blister fluid (SBF), saliva and urine in six healthy male subjects who were administered a 1-g dose intravenously. Serum levels in five subjects can be described according to a two-compartment open model; terminal half-life is 181±14 min. Volume of distribution (V_d) amounts to 15.3±1.61, serum clearance to 59±6 ml/min, renal clearance to 33±3 ml/min. Of the administered dose, 54% is renally excreted unchanged within 27 h. Unbound drug fraction in serum is 19.0% and in SBF 38.4%. Thus renal clearance of free cefodizime amounts to 172 ml/min, V_dss to 68.91 (free drug). Whereas cefodizime has not been detected in saliva samples, SBF concentration 3–9 h post administration parallel serum levels, amounting to 40% of the respective serum concentration. At 9 h, unbound cefodizime concentrations in SBF amount to 1.4±0.4 µg/ml, this value being well above the MIC_90% values of many clinically relevant bacteria.     

Pharmacokinetics of cimetidine in advanced cirrhosis

Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p<0.01); renal clearance (Cl_r) 296±100 vs 588±181 ml/min (p<0.01) and nonrenal clearance (Cl_nr) 97±111 vs 205±89 ml/min (p<0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (V_d) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between V_d and total plasma clearance (r=0.72, p<0.05). Volume of distribution in steady state (V_dss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.Part of this study has been reported as a Letter to the Editor, N Engl J Med (1982): 307, 187     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Human pharmacokinetics of tolfenamic acid,a new anti-inflammatory agent

Summary The pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent was studied in six healthy volunteers after an intravenous dose of 100 mg and oral doses of 100, 200, 400 and 800 mg. The disposition of intravenous tolfenamic acid could be described by two-compartment open model, with a central compartment volume (V_dc) of 5.6±0.31 (mean±SE), volume during -phase (V_d) of 31±21, and a total elimination rate constant (k₁₀) 1.6±0.1 h^–1. The terminal elimination half-life was 2.5±0.6 h and the total plasma clearance 155±15 ml/min. The elimination occured principally by extrarenal mechanisms, the recovery of unchanged drug together with is glucuronide in urine averaging only 8.8% of the intravenous dose. The binding of tolfenamic acid to plasma proteins averaged 99.7%. The gastrointestinal absorption had a mean half-life of 1.7±0.1 h. Based on comparison of areas under the plasma concentration time-curves after intravenous and oral administration, the biovailability of tolfenamic acid capsules averaged 60%. The rate and extent of absorption and the rate of elimination of tolfenamic acid were independent of dose.     

Pharmacokinetics of tolfenamic acid: Disposition in bile,blood and urine after intravenous administration to man

Summary To study its pharmacokinetics and especially its biliary excretion, ¹⁴C-tolfenamic acid 9.84 µCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7–10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V₁ of 3.67±0.68 l and V_ss of 8.0±1.0 l. The total plasma clearance of tolfenamic acid averaged 106±8 ml/min and t_1/2 was 1.38±0.32 h. A three compartment open model was required to describe the kinetics of total ¹⁴C. The plasma clearance of total ¹⁴C was 15.4±3.9 ml/min and its terminal half life averaged 19.0±4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1±0.3% of the dose, whereas the recovery of total ¹⁴C was 18.6±4.9%. The biliary clearances of tolfenamic acid and total ¹⁴C were 1.2±0.3 and 5.0±2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.     

Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites

Summary Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0–51 ml · min^–1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21±2.33 (SD) h whilst that in renal failure was 10.15±1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6±10.9 ml·kg^–1h^–1 which was significantly larger than in renal failure where it was 48.8±10.9 ml·kg^–1h^–1. V_d , V_{d ss} and V_c were not significantly different between the two groups. A linear relationship exists between , the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t_1/2 in normal patients was 8.33±2.0 h, whilst in the renal failure group it was 13.37±4.23 h. Total alkylating activity as measured by the nitrobenzylpyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.     

Factors affecting the kinetics of two benzothiazine non-steroidal anti-inflammatory medicines,piroxicam and isoxicam

Summary The pharmacokinetics of isoxicam and piroxicam were compared in 12 young adults (<40 years) and 12 elderly subjects (>65 years). After a single oral dose of 200 mg isoxicam or 20 mg piroxicam blood samples were taken for 168 h and the plasma drug concentrations determined by HPLC. The elimination half life of piroxicam for the adults was 57.1±16.4 h (mean ± SD; harmonic mean 52.9 h) and for the elderly subjects was 57.8±22.1 h (harmonic mean 52.1 h). The corresponding values after isoxicam were 34.3±13.6 h (harmonic mean 31.6) for the adults and 39.1±22.7 h (harmonic mean 33.5) for the elderly subjects. Similarly no differences were noted in either the AUC_0- after piroxicam (adults 154.1±52.2 µg·h/ml, elderly 163.6±99.1 µg·h/ml) and isoxicam (adults 642.7±241.9 µg·h/ml, elderly 787.9±613.1 µg·h/ml) or the apparent oral clearance of piroxicam (adults 2.39±0.80 ml/min, elderly 2.51±0.90 ml/min) and isoxicam (adults 5.84±2.04 ml/min, elderly 5.59±2.12 ml/min). One adult and two elderly subjects exhibited slower elimination of both medicines than the remainder of each group. However determination of the oxidation phenotype using sparteine metabolism showed that this was not a likely determinant of the reduced clearance.     

Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Pharmacokinetic interactions of timolol with vasodilating drugs,food and phenobarbitone in healthy human volunteers

Summary Pharmacokinetic interactions of oral timolol maleate 10 mg, with food (3566 kJ), single oral doses of prazosin 1 mg and dihydralazine 25 mg, and with a 1 week pretreatment with phenobarbitone 100 mg daily were examined in a randomized crossover study in 12 healthy volunteers. After fasting, the peak level (C_max=29.1±3.2 ng/ml; mean±SEM) was reached at 1.3±0.1 h (T_max). The total area under the serum concentration-time curve (AUC^0–) was 154.4±33.8 ng×h/ml, total clearance (Cl_tot) 751.5±90.6 ml/min, renal clearance (Cl_ren) 97.2±10.1 ml/min, elimination half-life (t_1/2) 2.9±0.3 h and 24-h recovery in urine (X _u ^0–24 ) 11.1±1.4% of the dose. Food and prazosin did not significantly affect the fate of timolol maleate. Dihydralazine enhanced C_max (38.2±4.6 ng/ml) only when compared to phenobarbitone treatment, and did not affect any other parameters. Phenobarbitone pretreatment somewhat lowered C_max (25.5±3.9 ng/ml), AUC^0– (117.5±22.1;p<0.05 vs food) and X _u ^0–24 (8.7±1.2%), evidently by increasing Cl_tot (957.5±116.9 ml/min;p<0.05 vs food), but it did not affect Cl_ren. It is concluded that the pharmacokinetics of timolol maleate can be altered to a limited extent in opposite directions by dihydralazine and phenobarbitone.     

Pharmacokinetics of acebutolol in patients with all grades of renal failure

Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p<0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p<0.001; NAM: r=0.954,p<0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (_bc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.     

Pharmacokinetics of quinine in African patients with acute falciparum malaria.

The pharmacokinetics of quinine were studied in six Nigerian patients during acute uncomplicated falciparum malaria and convalescent periods. An oral dose of 10 mg/kg quinine dihydrochloride administered 8hourly for 7 days gave parasite and fever clearance times of 36.0 ± 16.6 h and 18.0 ± 6.4 h, respectively. From the individual quinine plasma profiles the mean plasma concentration of quinine at the time of parasite clearance was estimated as 4.5 ± 1.1 g/ml. Plasma quinine levels during malaria rose rapidly reaching a peak around the second and third days and declining thereafter as patients improved clinically. In acute malaria plasma quinine levels were more than two-fold higher than in convalescence; the mean AUC(0-12) in malaria was 37.9 ± 14.7 g.h/ml compared to 17.9 ± 8.5g.h/ml in convalescence. The apparent oral clearance (CL/F) and volume of distribution (Vd/F) duri ng the acute phase of the malaria (1.9 ± 0.7 ml/min/kg and 1.8 ± 0.9 l/kg, respectively) were significantly lower than in convalescence (4.5 ± 2.1 ml/min/kg and 4.2 ± 3.2 l/kg). The present data suggest that malaria parasites in African patients are still very sensitive to quinine and that the current dosage of quinine is effective for the treatment of acute falciparum malaria in African patients without augmenting therapy with any other drug such as tetracycline or sulphadoxine-pyrimethamine. It also confirms that malaria significantly alters the pharmacokinetics of quinine in humans.     

High-Performance Liquid Chromatographic Determination of 2′, 3′ -Didehydro-3′ -deoxythymidine (d4T) in Human and Rabbit Plasma and Urine and Its Application to Pharmacokinetic Studies in the Rabbit

A rapid and sensitive liquid chromatographic assay for 2,3-didehydro-3-deoxythymidine (d4T) in plasma and urine is described. This assay uses thymidine oxetane (TO), a synthetic precursor of d4T, as internal standard. Sample preparation involves a simple extraction of plasma or urine with 5% isopropyl alcohol in methylene chloride. The method is specific and sensitive, allowing a linear response over a 2000-fold range of concentrations in human plasma (5 ng/ml to 10 µg/ml) and urine (50 ng/ml to 100 µg/ml). This assay, developed for human plasma and urine, is also applicable to rabbit samples with minor modification. Intravenous bolus doses of 10 mg/kg d4T to rabbits showed that the plasma concentration–time profile followed a biexponential decay. Estimates of the distribution and elimination half-lives were 6.7 ± 0.9 and 51 ± 6 min, respectively. The total-body and renal clearances were 23.4 ± 3.6 and 8.82 ± 3.9 ml/min · kg, respectively. That the renal clearance exceeds the glomerular filtration rate in the rabbit suggests that d4T is actively secreted in the renal tubule. The fraction excreted unchanged in the urine was 36 ± 8%. Similar results were obtained in the same rabbits at steady state during constant-rate intravenous infusion. Noncompartmental analysis estimates of the MRT and V _dss were 46 ± 5 min and 1.08 ± 0.13 L/kg, respectively.     

Stereoselective analysis of the disposition of tosufloxacin enantiomers in man

Summary The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6±0.3 [mean ± SEM] h for (+)-tosufloxacin vs 2.4±0.2 h for (–)-tosufloxacin), elimination half-life (3.61±0.24 h vs 3.49±0.23 h), and area under the curve (2.78±0.19 h·g/ml vs 2.87±0.19 h·g/ml); however, peak concentration (0.40±0.03 g/ml vs 0.44±0.03 g/ml), renal clearance (226±10 ml/min vs 202±10 ml/min), and urinary recovery (35.4±2.2% vs 32.4±1.9%) differed significantly between enantiomers.     

Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin andβ-methyldigoxin

Summary Five healthy volunteers received digoxin 0.4 mg or -methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and -methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for -methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for -methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of -methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of -methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.Abbreviations of parameters D dose - EST estimated disposition rate constant (day^–1) semilog curve fit - KTOT total disposition rate constant (day^–1) NONLIN fit - KREN renal disposition rate constant (day^–1) NONLIN fit - VOL volume of distribution (liters) NONLIN fit - CTOT total clearance (ml/min) - CREN renal clearance (ml/min) - BMIN body stores (µg) before next dose in steady state - CCR creatinine clearnace (ml/min) - CR/CT fraction renally excreted - CR/CCR renal drug clearance versus creatinine clearance - T/2 half life (days) - BMIN/D extent of accumulation This study was supported by Bundesministerium für Jugend, Familie und Gesundheit, Federal Republic of Germany.     

Interaction of bisoprolol with cimetidine and rifampicin

Summary In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (C _max ^ss ) of the beta-blocker were 55.5±6.4 ng/ml (x±SEM), area under the plasma level-time curve (AUC) was 597±70 ng/ml.h, total body clearance (CL) 15.8±1.8 l/h and elimination half-lives (t_1/2) 10.1±1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in C _max ^ss (43.0±6.9 ng/ml), AUC (397±54 ng/ml·h) and t_1/2 (6.2±0.4 h). Accordingly, total body clearance increased to 23.8±2.51/h (p<0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.     

Single-dose toxicokinetics ofN-nitrosomethylethylamine andN-nitrosomethyl (2,2,2-trideuterioethyl)amine in the rat

To investigate the origins of an organotropic shift toward increasing esophageal carcinogenicity and DNA alkylation caused by -trideuteration of the hepatocarcinogen,N-nitrosomethylethylamine (NMEA), the single-dose toxicokinetics of NMEA andN-nitrosomethyl(2,2,2-trideuterioethyl)amine (NMEA-d ₃) has been characterized in 8-week-old male Fischer 344 rats by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 mol/kg to rats revealed biphasic first order elimination with a terminal half-life of 9.46 ± 0.69 min for unchanged NMEA and 28.9 ± 2.4 min for total radioactivity. Extensive conversion to polar metabolites was observed in the chromatograms. The systemic blood clearance and apparent steadystate volume of distribution for unchanged NMEA were 39.9 ± 4.6 ml/min/kg and 496 ± 36 ml/kg, respectively. There was negligible plasma protein binding and no detectable NMEA was excreted unchanged in the urine. Larger doses given by gavage indicated a systemic bioavailability of 25 ± 1%. Similar doses of NMEA-d ₃ given to other groups of rats revealed no significant differences in any of the toxicokinetic parameters. NoN-nitrosomethyl (2-hydroxyethyl)amine was found as a detectable metabolite of NMEA or NMEA-d ₃ in any of the blood or urine samples which were analyzed. When considered together, the data suggest that previously observed differences in organ specificity for the carcinogens, NMEA and NMEA-d ₃, are not due to differences in the total amounts of nitrosamine reaching particular tissues, but may have other localized causes such as differences in the enzymes responsible for metabolism which are present in each tissue. Such differences may make too small a contribution to the total systemic clearance to be detectable in that parameter, but at the level of the fraction of a dose that alkylates DNA they may be important.     

Boric acid single dose pharmacokinetics after intravenous administration to man

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cl_tot 54.6±8.0 ml/min/1.73 m², t_1/2 21.0±4.9 h and distribution volumes V₁, V₂, and V₃: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.     

Effect of rifampicin treatment on the kinetics of mexiletine

Summary To study the effects of enzyme induction on its pharmacokinetics, a single oral dose of the new antiarrhythmic agent mexiletine hydrochloride 400 mg was administered to 8 healthy volunteers before and after treatment with rifampicin 300 mg b.i.d. for ten days. The absorption and distribution of mexiletine were not changed after rifampicin, but its elimination half-life fell from 8.5±0.8 h (mean±SE) to 5.0±0.4 h (p<0.01), and its nonrenal clearance increased from 435±68 ml/min to 711±101 ml/min (p<0.01). The mean renal clearance of mexiletine did not change, but it showed an exponential correlation with urinary pH. The amount of unchanged mexiletine excreted in urine over two days decreased from 32±7 to 18±3 mg (p<0.01). The half-life of antipyrine fell from 11.8±0.4 to 5.5±0.3 h and its clearance increased from 40±3 ml to 74±3 ml/min (p<0.01). There was a significant (p<0.05) positive linear correlation between both the half-lives and the clearances of antipyrine and mexiletine. The clearances were positively correlated with serum -glutamyl transpeptidase. The results suggest that the dosage of mexiletine should be adjusted when enzyme inducing drugs are started or stopped during therapy with it.     

The Pharmacokinetics and Electroencephalogram Response of Remifentanil Alone and in Combination with Esmolol in the Rat

Purpose. The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective -blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. Methods. Sprague-Dawley rats (N = 8, Wt. = 325 ± 15g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 g/ kg/min), and REMI & ES (15 g/kg/min and 600 g/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1–50 Hz) for spectral edge (97%). Results. No significant differences (p < 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 ± 148 ml/ min kg) or Vd (REMI = 286 ± 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid E_max PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean E_max and EC₅₀ after REMI were 18.0 ± 6.0 Hz and 32 ± 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. Conclusions. At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.