Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes

The cytochrome P-450dbl isozyme (P-450bdl) is responsible for the genetic sparteine-debrisoquine type polymorphism of drug oxidation in humans. To investigate the relationship between mexiletine oxidation and the activity of this isozyme, cross-inhibition studies were performed in human liver microsomes with mexiletine and dextromethorphan, a prototype substrate for P-450dbl. The formation of hydroxymethylmexiletine and p-hydroxymexiletine, two major mexiletine metabolites, was competitively inhibited by dextromethorphan. Mexiletine competitively inhibited the high affinity component of dextromethorphan O-demethylation. In addition, there was a good agreement between the apparent Km values for the formation of both mexiletine metabolites and the high affinity component of dextromethorphan O-demethylation and their respective apparent Ki values. Several drugs were tested for their ability to inhibit mexiletine oxidation. Quinidine, quinine, propafenone, oxprenolol, propranolol, ajmaline, desipramine, imipramine, chlorpromazine and amitryptiline were competitive inhibitors for the formation of hydroxymethylmexiletine and p-hydroxymexiletine as for prototype reactions of the sparteine-debrisoquine type polymorphism. Amobarbital, valproic acid, ethosuximide, caffeine, theophylline, disopyramide and phenytoin, known to be non-inhibitors of P-450dbl activity, were found not to inhibit the formation of these mexiletine metabolites. Moreover, the formation of both metabolites was strongly inhibited by an antiserum containing anti-liver/kidney microsomes antibodies type I (anti-LKMI) directed against P-450dbl. These data suggest that the formation of two major metabolites of mexiletine is predominantly catalysed by the genetically variable human liver P-450dbl.     

The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation.

1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O-demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4-hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = -0.83; P = 0.006 and rs = -0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine-type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Frequency-dependent effects of several class I antiarrhythmic drugs on Vmax of action potential upstroke in canine cardiac Purkinje fibers

Vmax of the action potential upstroke in canine cardiac Purkinje fibers was studied in the presence of seven class I antiarrhythmic drugs--lidocaine (4 micrograms/ml), mexiletine (4 micrograms/ml), propranolol (0.9 micrograms/ml), procainamide (30 micrograms/ml), quinidine (5 micrograms/ml), flecainide (4 micrograms/ml), and disopyramide (3.1 micrograms/ml)--at constant cycle lengths (CCL) and after abrupt changes in cycle length (ACCL). The time constant of Vmax recovery after ACCL at a basic cycle length of 500 ms was 0.09 +/- 0.01 s for lidocaine, 0.18 +/- 0.03 s for mexiletine, 1.35 +/- 0.20 s for propranolol, 4.4 +/- 0.8 s for procainamide, 8.3 +/- 1.2 s for quinidine, 11.0 +/- 0.9 s for flecainide, and 37.9 +/- 9.4 s for disopyramide. These values were similar to those reported by others in guinea pig papillary muscle, and, with the exception of flecainide, conformed to the scheme proposed by Courtney (J Mol Cell Cardiol 1980; 12:1273-86) based on the molecular weight and lipid solubility hypothesis. Each drug altered the Vmax differently at CCL from after ACCL at the same diastolic intervals. The magnitude of these differences and the range of diastolic intervals at which they were present varied among different drugs. These observations explain differences in the drug effects on the Vmax of the regularly and prematurely occurring depolarizations. In the presence of lidocaine and mexiletine, the recovery kinetics of Vmax were not altered by CCL within the 300-1,500-ms range, and the magnitude of Vmax depression was not influenced by action potential duration within the 200-270-ms range.     

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.     

Hepatic and renal clearances of probenecid in the rat

The elimination kinetics of probenecid in the rat was studied by using an in vitro liver perfusion system to estimate its basic elimination and in vivo to estimate its renal excretion by catheterization of the urinary bladder. In the liver perfusion study different amounts of probenecid were added to the perfusion medium yielding different initial concentrations (40, 200 and 400 micrograms/ml), and 4 different intravenous bolus doses (50, 75, 100 and 200 mg/kg) were administered in vivo to rats in order to evaluate the renal excretion. The results obtained were described by one-compartment models, with Michaelis-Menten elimination by the liver Vm = 67.4 +/- 14.0 (SD) micrograms/min and a slightly decreasing Km with increasing initial concentrations [from 76.5 +/- 9.0 to 53.2 +/- (SD) 18.4 micrograms/ml]. The excretion by the kidney was characterized by a saturable pathway in parallel with first-order elimination, the maximum rate of the active transports Tm = 0.04 +/- (SD) 0.09 micrograms/min, Km,r = 100.3 +/- (SD) 12.3 micrograms/ml and a linear renal clearance of 0.0008 +/- (SD) 0.0002 ml/min.     

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, metabolism and excretion of megazol, a new potent trypanocidal drug in animals.

The pharmacokinetics of megazol (CAS 19622-55-0) was investigated after intraperitoneal and oral administration of the drug (80 mg/kg) to mice. The plasma levels were significantly higher after oral administration of drug than after intraperitoneal route (33.8 micrograms/ml compared with 19.0 micrograms/ml for Cmax, 158714 micrograms.h/l compared with 96057 micrograms.h/l for AUC). When suramin (CAS 145-63-1) was administered 24 h before oral administration of megazol, megazol absorption was accelerated (2 h compared with 4 h for Tmax) but the amount absorbed was lower (19.9 micrograms/ml compared with 33.8 micrograms/ml for Cmax and 95547 micrograms.h/l vs 158714 micrograms.h/l for AUC). In the infected mice previously treated with suramin, all estimated pharmacokinetic parameters of plasma megazol were significantly modified, in particularly an increase in the apparent volume of distribution (5.6 l/kg compared with 0.9 l/kg) with a prolongation of the elimination half-life (3 h compared with 0.7 h) of megazol. Excretion of the total radioactivity of megazol was also evaluated after oral administration of 3H-megazol to rats. Total radioactivity was eliminated predominantly via the urinary route (80%) vs. 10.5% in the faeces, 9.5% remaining in the body 8 days after dosing. When unlabelled megazol was orally administered to rats with absence or presence of suramin, megazol recovered in urine and faeces 72 h dosing was: 55.7%/2% vs 20.6%/1.6%, respectively. In the urine, unchanged megazol was present as characterized by LC-MS/MS as well as 4 unknown metabolites. This study indicates that suramin significantly affects the pharmacokinetics of megazol and its elimination.     

A study of the absorption and excretion of fosfomycin sodium in children

Fosfomycin sodium (FOM-Na, Forocyle-S) was administered at 25 mg/kg or 50 mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analysis was carried out using the one-compartment model. 1. Average concentrations in the blood serum after injections with 25 mg/kg and 50 mg/kg were 55.3 +/- 6.3 micrograms/ml and 118.8 +/- 31.1 micrograms/kg 30 minutes after injection, respectively, and their half-lives were 1.04 +/- 0.15 hours and 0.98 +/- 0.17 hours, respectively. Six hours after injection, the levels were 2.7 +/- 1.6 micrograms/kg and 6.2 +/- 5.5 micrograms/kg, respectively. With 1 hour intravenous drip infusion of 25 mg/kg and 50 mg/kg, average concentrations the blood serum were 34.2 +/- 14.9 micrograms/ml and 89.7 +/- 6.7 micrograms/ml, respectively, and their half-lives were 0.87 +/- 0.24 hour and 0.69 +/- 0.10 hour, respectively. Six hours after the administration, the levels were 2.7 +/- 1.8 micrograms/ml and 6.7 +/- 0.8 micrograms/ml. There was a clear dose response in the concentration levels in the blood in those given the drug at 25 mg/kg and 50 mg/kg in either method of administration. 2. Average levels in urine after injection of 25 mg/kg and 50 mg/kg were 5,778 +/- 2,257 micrograms/ml and 6,268 +/- 3,329 micrograms/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701 +/- 765 micrograms/ml and 1,588 +/- 1,324 micrograms/ml, respectively. Average excretion, rates into the urine were 72.8 +/- 11.0 and 73.9 +/- 11.1%, respectively. In case of 1 hour drips infusion of 25 mg/kg and 50 mg/kg, average concentrations in the urine 0-2 hours after administration were 3,570 +/- 1,540 micrograms/ml and 11,800 micrograms/ml, respectively, and averages for 4-6 hours were 211 +/- 124 micrograms/ml and 1,300 micrograms/ml. Average rates of excretion into the urine for the first group was 57.9 +/- 16.3% and the second group was 78.4%. Clear dose response was observed in changes of drug concentration levels in the urine with 25 mg/kg and 50 mg/kg doses through either administration method, and in terms of excretion into the urine, no noticeable differences were observed between the different amounts administered or different administration methods.(ABSTRACT TRUNCATED AT 400 WORDS)     

Transfer of injected sulbactam/cefoperazone into burn blister fluid

Transfer of sulbactam/cefoperazone (SBT/CPZ) into the burn blister fluid was studied in 10 burn patients after one shot intravenous injection of 50 mg/kg SBT/CPZ (CPZ 25 mg/kg, SBT 25 mg/kg). CPZ and SBT concentrations in serum and burn blister fluid were determined using bioassay and high performance liquid chromatography (HPLC). The concentration of CPZ in serum reached 109.5 +/- 9.2 micrograms/ml (mean +/- S.E.) at 0.25 hour after injection, and decreased to 6.8 +/- 2.3 micrograms/ml after 8 hours. The concentration of CPZ in burn blister fluid peaked at 4 hours and reached 28.2 +/- 8.0 micrograms/ml. The concentration of SBT in serum reached 75.7 +/- 8.3 micrograms/ml at 0.25 hour after injection, and decreased to 2.3 +/- 0.7 micrograms/ml after 8 hours. The peak concentration of SBT in burn blister fluid was 13.5 +/- 1.8 micrograms/ml at 3 hours. The data obtained were analysed pharmacokinetically. Cmax of CPZ and SBT levels in burn blister fluid were calculated to be 30.4 micrograms/ml and 13.6 micrograms/ml, respectively. The AUC0-8 hrs. (area under the burn blister fluid concentration of drug-time curve between 0 and 8 hours after injection), absorption rate constant (ka) and therapeutic AUC (AUC where drug concentrations were above minimum effective concentration) of CPZ were calculated to be 194.0 micrograms.hr/ml, 1.52 hr-1 and 97.1 micrograms.hr/ml (0.3-11.1 hours), respectively. The AUC0-8 hrs. and ka of SBT were also calculated as 68.3 micrograms.hr/ml and 0.62 hr-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and clinical studies on amikacin in neonates

Pharmacokinetic and clinical studies on amikacin (AMK) were performed in neonates and the results obtained are summarized as follows. 1. After intramuscular injection of single doses of AMK at 3 mg/kg, peak serum levels were 6.8 micrograms/ml in a 2-day-old neonate and 7.0 micrograms/ml in a 20-day-old neonate. Serum levels of AMK in the above 2 neonates at 8 hours after injection were 1.5 micrograms/ml and 1.4 micrograms/ml, respectively, and the half-life of AMK was 3.3 hours. After intramuscular injection of single doses of 4 mg/kg of AMK, the mean peak serum level was 8.1 +/- 1.1 micrograms/ml, and half-lives of AMK were 6.1 hours in a 1-day-old neonate and 4.0 hours in a 3-day-old neonate. The mean peak serum level of AMK reached at 1 hour after intramuscular administrations at single dose of 6 mg/kg was 10.5 +/- 0.5 micrograms/ml in a 3-day and a 4-day-old neonates. Serum levels at 8 hours after administrations were 3.1 micrograms/ml and 2.8 micrograms/ml, in the 3-day and the 4-day-old neonates, respectively. Half-lives of AMK in sera were 3.9 hours in the 3-day-old neonate and 3.5 hours in the 4-day-old neonate. 2. In three 2-day-old neonates, the mean peak serum level of AMK after an intravenous drip infusion for 30 minutes at single dose of 3 mg/kg was 10.0 +/- 1.1 micrograms/ml at the end of infusion and serum levels decreased to 2.3 +/- 0.6 micrograms/ml at 6.5 hours after infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline: pharmacokinetics, metabolism and urinary excretion in dogs

The disposition of theophylline (aminophylline) administered either parenterally or orally to anesthetized dogs was studied. Pharmacokinetics of theophylline (8.2 mg/kg, n = 10) following intravenous administration could be analyzed by a two-compartment open model. The half-time (T1/2 beta) of theophylline was 5.63 +/- 0.83 hr, and the volume of distribution (Vd) was 0.73 +/- 0.04 l/kg. The elimination rate constant was 0.37 +/- 0.05 hr-1. Two metabolites of theophylline were isolated from urine and identified as 3-methyl xanthine (3-MX) and 1,3-dimethyl uric acid (1,3-DMU) by HPLC. The dogs excreted about 85% (n = 4) of the dose in urine in 24 hr. The majority (2/3) was excreted as changed theophylline, i.e., 3-MX 40.2 +/- 3.5% and 1,3-DMU 26.2 +/- 4.3%, while unchanged theophylline amounted to 18.2 +/- 2.4%. Absorption of theophylline (8.2 mg/kg, n = 5) administered intramuscularly was good as indicated by its high bioavailability (101.9 +/- 6.5%), but the value of bioavailability was low in oral administration (72.8 +/- 11.8%, n = 5). The percentage of protein binding (about 44%, n = 3-7) did not change by increasing the serum concentration (8.2-24.6 micrograms/ml).     

Pharmacokinetics, metabolism and elimination of itanoxone in humans

The pharmacokinetics, metabolism and elimination of Itanoxone was studied after a single oral administration of the carbon-14-labelled drug (500 mg) in four male volunteers. The drug was absorbed fairly rapidly with a mean peak plasma level of 10.3 +/- 1.3 micrograms/ml between 3 and 4 hours after dosing. The pharmacokinetics can be described by a two-compartment open model with the central compartment consisting of the extracellular fluid. The mean elimination half-life was 19.4 +/- 8.5 hours. Two metabolites as well as unchanged Itanoxone were detected in plasma. Approximately 37% of the radioactivity was excreted over a five-day period in the urine and 50% in the faeces. There were only traces of free metabolites in the urine as the rest of the radioactive metabolites were associated with glucuronide conjugates. These conjugates consisted of Itanoxone and up to six metabolites. Five of these metabolites have been tentatively identified by comparison of their chromatographic properties by TLC and HPLC with a number of reference compounds. After repeated administration of Itanoxone (250 mg b.i.d.) the maximum level at steady state was about 7 micrograms/ml and the minimum level, 0.6 micrograms/ml. The mean area under the plasma level time curve was 35% higher than in the single dose study after correction for dose.     

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.     

Pharmacokinetic and clinical studies on cefmenoxime in neonates and infants

Pharmacokinetic and clinical studies on cefmenoxime (CMX) in neonates and infants were conducted. 1. CMX 20 mg/kg was administered by intravenous bolus injection to 6 neonates (with ages 2 to 20 days) and 5 infants (with ages 36 to 107 days) and its serum concentration and urinary excretion rates were determined. In the neonates, serum concentrations of CMX after intravenous administration reached peak levels of 48.2 to 90.7 micrograms/ml (mean 70.4 +/- 14.3 micrograms/ml) in 1/4 hour, then declined with half-lives of 1.27 to 5.19 hours (mean 2.28 +/- 1.56 hours), and were 3.6 to 16.9 micrograms/ml (mean 8.3 +/- 6.0 micrograms/ml) at 6 hours. In the infants, serum concentrations at 1/4 hour were 67.5 to 111.0 micrograms/ml (mean 95.5 +/- 18.0 micrograms/ml); half-lives were 0.64 to 0.94 hour (mean 0.81 +/- 0.13 hour); and the serum concentrations at 6 hours were 0.2 to 1.1 micrograms/ml (mean 0.7 +/- 0.4 micrograms/ml). Mean peak serum concentrations in the neonates tended to be lower than those in the infants, but higher than those in children. Regarding the age differences of serum concentrations due to age in the neonates, their peak levels tended to be lower in younger ones. Half-lives were shorter in older subjects and, in early infancy, approached values observed in children. Urinary recovery rates in the first 6 hours after intravenous administration ranged from 43.6 to 87.5% (mean 61.6 +/- 14.6%) in the neonates and from 52.1 to 90.8% (mean 78.0 +/- 15.1%) in the infants. Thus, recovery rates were high even in younger subjects and tended to be higher in older subjects. 2. CMX was administered to 27 neonates and 4 infants to investigate its clinical effect, bacteriological effect and side effects. Clinical efficacy ratings of the drug in 19 neonate cases that could be evaluated (1 with purulent meningitis, 2 with suspected septicemia, 1 with acute bronchitis, 12 with acute pneumonia, 1 with impetigo, 1 with periumbilical abscess and 1 with acute pyelonephritis) were "excellent" in 14 cases, "good" in 4, and "poor" in 1. The efficacy rate covering "excellent" and "good" was 94.7%. In 4 infants (2 with acute pneumonia, 1 with periumbilical abscess and 1 with acute pyelonephritis), "excellent" was obtained in 2 cases and "good" in 2 cases. Thus, all the cases showed "good" or higher ratings. Bacteriologically, 1 strain of Staphylococcus aureus and 3 strains of Escherichia coli in neonates were eradicated while, in infants, 1 strain of S. aureus persisted but 1 of E. coli was eradicated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Plasma histamine and clinical tolerance to infused histamine in normal, atopic and urticarial subjects

Five subjects with a recent history of urticaria (U), five atopic (A) subjects and a non-atopic (NA) control group were given intravenous infusions of histamine starting at 0.05 micrograms/kg/min, increasing by 0.05 micrograms/kg/min every 30 minutes to a maximum of 0.35 micrograms/kg/min. Plasma histamine levels were monitored every 15 minutes. The infusion was stopped when an objective clinical endpoint was reached, involving either evidence of peripheral vasodilatation (rise of skin temperature by at least 1 degree C) or a 20% fall of peak expiratory flow rate. There were no significant differences in resting plasma histamine in the three groups. Those with urticaria reached the clinical endpoint at a lower infusion rate than non-atopic subjects (U 0.22 +/- 0.02 micrograms/kg/min; A 0.26 +/- 0.02 micrograms/kg/min; NA 0.32 +/- 0.2 micrograms/kg/min. p less than 0.008) they also received a lower total histamine dose (U 1.12 +/- 0.33 mg; A 1.42 +/- 0.38 mg, NA 2.2 +/- 0.51 mg, p less than 0.008). Atopic subjects with a history of asthma, eczema or rhinitis also tolerated histamine poorly, some subjects reaching a clinical endpoint while the plasma histamine level was still relatively low (U 1.52 +/- 0.4 ng/ml, A 0.85 +/- 0.19 ng/ml, NA 1.4 +/- 0.44 ng/ml, p = 0.05). After the histamine infusion was stopped, the fall in the blood level of histamine was slower in urticarial subjects than in the other two groups, with a half-life of 6.2 +/- 1.3 min (A 3.0 +/- 1.2 min, NA 4.0 +/- 0.7 min, p less than 0.02). There were thus differences in the metabolism of histamine in our non-atopic urticarial subjects and increased histamine sensitivity in atopic subjects which require further study.     

Pharmacokinetic and clinical studies of ceftriaxone in neonates

Pharmacokinetic and clinical studies on ceftriaxone (CTRX) in mature and premature neonates were carried out. The results are summarized as follows. The mean serum peak level of CTRX after intravenous administration at a single dose of 10 mg/kg in 4 to 13 day-old-neonates was 34.1 +/- 11.4 micrograms/ml at 30 minutes. The mean serum level at 12 hours after dosage was 11.1 +/- 2.1 micrograms/ml. The mean half-life time was 11.6 +/- 1.4 hours. Mean serum peak levels of CTRX after intravenous administration at a single dose of 20 mg/kg were 64.6 +/- 15.4 micrograms/ml in 1 to 3 day-old-neonates, 44.6 +/- 1.1 micrograms/ml in 5 day-old-neonates at 30 minutes. Mean serum levels at 12 hours after dosage in these two groups of neonates were 16.4 +/- 4.8 micrograms/ml and 12.4 +/- 2.5 micrograms/ml, respectively. Mean half-life times were 13.7 +/- 3.7 hours in 1 to 3 day-old-neonates and 10.2 +/- 1.3 hours in 5 day-old-neonates. CTRX was clinically effective in a case of urinary tract infection. No side effect was observed except an elevation of GOT.     

The diffusion of cefazedone into heart muscle, prostatic and skin tissue and into bile

The diffusion of cefazedone into human heart muscle, prostatic and skin tissue as well as bile fluid was investigated. 40 to 80 min after a single injection of 100 mg/kg (n = 14) the concentration in the heart muscle was between 10.8 and 85.5 micrograms/g. The respective serum levels were between 117 and 168.1 micrograms/ml. The single i.v. injection of 2 g cefazedone resulted within 30 min in a mean concentration of 34.63 +/- 9.75 micrograms/g in the prostatic tissue and in serum levels of 139.07 +/- 39.68 micrograms/ml (n = 14). In 5 patients additional values were estimated after 60 min. At this time the antibiotic concentrations were 24.92 +/- 1.31 micrograms/g in the tissue, with simultaneous serum levels of 87.25 +/- 20.86 micrograms/ml. 1 h after a 500 mg i.v. dose, concentrations in bile taken from T-tube were between 71.4 and 210 micrograms/ml. After 2 h there was a mean level of 83.2 micrograms/ml which was significantly above the serum concentrations at the same time (1 h = 35.25 +/- 7.17; and 2 h = 20.5 micrograms/ml). The bile concentration of 2 patients taken 5 h after cefazedone injection was 4.95 and 11.6 micrograms/ml. The cefazedone concentrations in the skin were estimated mainly in biopsies from granulating leg ulcer tissues. The mean concentrations in 4 cases were 120 +/- 28.7 micrograms/g 3 h after i.v. injection of 2 g cefazedone. The simultaneous serum levels were between 14.85 and 68.2 micrograms/ml, in one patient with extreme venous stasis the tissue concentration was only 8.1 micrograms/g. Cefazedone should be regarded as an antibiotic with excellent penetration into tissues.     

Transfer of fosfomycin into human burn blister fluid and its pharmacokinetic analysis

Fosfomycin (FOM) (50 mg/kg) was administered to burned patients by intravenous bolus injection. Burn blister fluid and serum were taken during 8 hours after injection, and concentrations of FOM in burn blister fluid and serum were determined by bioassay using Proteus sp. (MB-838) as the test organism. The serum concentrations of FOM were 257 +/- 34.6 micrograms/ml at 15 minutes, 222 +/- 34.8 micrograms/ml at 30 minutes, 166 +/- 34.6 micrograms/ml at 1 hour, 114 +/- 43.9 micrograms/ml at 2 hours, 79.5 +/- 34.9 micrograms/ml at 3 hours, 63 +/- 36.4 micrograms/ml at 4 hours, 44.3 +/- 27.6 micrograms/ml at 5 hours, 29.6 +/- 20.9 micrograms/ml at 6 hours and 17.9 +/- 12.8 micrograms/ml at 8 hours after the injection. FOM concentrations in burn blister fluid were 64.4 +/- 18.1 micrograms/ml at 30 minutes, 77 +/- 26.0 micrograms/ml at 1 hour, 71.6 +/- 24.7 micrograms/ml at 2 hours, 64.8 +/- 23.6 micrograms/ml at 3 hours, 43.2 +/- 8.8 micrograms/ml at 4 hours, 24.8 +/- 7.9 micrograms/ml at 6 hours and 17.9 +/- 10.5 micrograms/ml at 8 hours after the injection. The obtained data were analysed pharmacokinetically. The serum levels were analysed by a two-compartment model, and the transfer of FOM into burn blister was analysed by a modified deconvolution method. In results, Tmax and Cmax of FOM levels in burn blister fluid were calculated as 1.3 hours and 80.9 micrograms/ml, respectively. The transfer rate constant of FOM from serum to burn blister fluid (K1) and that from burn blister fluid to serum (K2) were calculated as 0.612 hr-1 and 1.10 hr-1, respectively.     

Pharmacokinetic, bacteriological and clinical studies of ceftizoxime in neonates

Pharmacokinetic, bacteriological and clinical studies of ceftizoxime (CZX) were performed in neonates. 1. Serum concentrations and urinary excretion of CZX were investigated in 12 neonates ranging ages from 1 to 27 days (gestational age, 35-41 weeks; birth weight, 2,150-4,030 g) and 2 infants ranging ages from 55 to 57 days (gestational age, 39-40 weeks; birth weight, 2,320-2,650 g). Each of the subjects was given a single intravenous dose of 20 mg/kg by one shot. Serum concentrations of CZX in the neonates were 24.9-53.7 micrograms/ml at 1/4 hour after intravenous injection, with an average of 40.6 +/- 7.6 micrograms/ml. Serum half-lives of CZX were 1.32-4.75 hours and averaged 2.60 +/- 1.06 hours. Serum concentrations ranged from 2.01 to 14.6 micrograms/ml at 6 hours after injection with an average of 7.70 +/- 3.89 micrograms/ml. In the 2 infants, serum concentrations were 42.0 and 46.2 micrograms/ml at 1/4 hour (average: 44.1 +/- 3.0 micrograms/ml), and 2.91 and 5.04 micrograms/ml at 6 hours after injection (average: 3.98 +/- 1.51 micrograms/ml). Half-lives were 1.54 hours in 1 infant and 1.93 hours in the other (average: 1.74 +/- 0.28 hours). Furthermore, 6-hour urinary recovery rates were 28.5-71.7% (average: 49.3 +/- 12.8%) in the neonates and 42.1-55.5% (average: 48.8 +/- 9.5%) in the infants. The above results suggest that the following 3 points are accepted; 1) peak serum concentrations (at 1/4 hour) in neonates were similar to those in infants and older children irrespective of age (days after birth). 2) Serum half-lives of CZX in neonates shortly after birth were 4 or 5 times longer than those in older children, but decreased rapidly with the advance of day-ages. The half-life in neonates of 2 weeks of age or so became shorter to about twice the normal value in infants. Furthermore, half-lives of the drug in those at an age of the first half of infancy were similar to those in older children. 3) The urinary excretion rates tended to be somewhat low with neonates soon after birth, but became very similar to those in infants and older children at a relatively early stage.(ABSTRACT TRUNCATED AT 400 WORDS)     

The disposition and metabolism of 14C-tiaramide . HCl in man

The disposition and metabolism of 14C-tiaramide HCl was examined in four healthy male volunteers, after administration of a 200-mg dose in solution. The mean cumulative recovery of administered radioactivity was 91.3 +/- 2.9% (mean +/- SD) in urine an 6.0 +/- 1.5% in feces. The elimination was rapid, with 83.9% of the radioactivity extracted in urine in the first 12 hr. The unchanged tiaramide serum concentration curve showed monoexponential elimination with a half-life of 1.3 hr. Peak serum levels, of 1.6-2.2 micrograms/ml were attained between 0.5 and 1.5 hr after dosing. Tiaramide was extensively metabolized, with less than 1% excreted unchanged. Urinary metabolites (80-95% of the dose) were identified by mass-spectral comparison to authentic standards. Biotransformation resulted in production of the N-acetic acid N-oxide, N-acetic acid, O-glucuronide, N-oxide, and desethanol metabolites of tiaramide.