Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

INTRODUCTION: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access. MATERIALS AND METHODS: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated. RESULTS: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively). CONCLUSION: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.

Single-dose pharmacokinetics of lomefloxacin in patients with normal and impaired renal function.

The quinolone antibiotic lomefloxacin was administered as a 400 mg single oral dose to 12 subjects with renal impairment (creatinine clearance 5-65 mL/min/1.73 m2) and to 13 healthy subjects (creatinine clearance 80-135 mL/min/1.73 m2). The concentrations of lomefloxacin in plasma and urine were determined by high-pressure liquid chromatography up to 48 hours post-administration. Linear correlations were found between lomefloxacin plasma and renal clearances and creatinine clearance. The mean nonrenal clearance of lomefloxacin (approximately 32 mL/min/1.72 m2) was not influenced by renal function. The mean plasma clearances of lomefloxacin in healthy subjects and in a subgroup of patients with severe renal impairment (creatinine clearance 5-15 mL/min/1.73 m2) were 209 and 43 mL/min/1.73 m2, respectively. The decrease in plasma clearance of lomefloxacin was explained fully by the decrease in renal clearance. The elimination half-life of lomefloxacin increased significantly with the degree of renal impairment, from 7.5 hours in normal subjects to 26.9 hours in subjects with severe renal impairment. The maximum serum concentration and the time to maximum serum concentration were not significantly affected by renal function. The pharmacokinetics of lomefloxacin are dependent on renal function, and appropriate dosage adjustment is necessary when creatinine clearance is less than 30 mL/min/1.73 m2.

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.

Comparison of the serum and tissue concentrations of cefuroxime from cefuroxime axetil and phenoxymethylpenicillin in patients undergoing tonsillectomy.

In the study described, the pharmacokinetics of two oral betalactams, cefuroxime axetil and phenoxymethylpenicillin, were compared with respect to their penetration into tonsil tissue. Seventeen patients were given cefuroxime axetil 500 mg single dose and 16 patients were given phenoxymethylpenicillin 650 mg single dose, at different time intervals before tonsillectomy. The tonsils were freeze-dried and the drug concentrations in serum and tissue determined by a high performance liquid chromatographic method. Cefuroxime axetil showed a slightly better penetration ratio (mean 35%, median 32%) than phenoxymethylpenicillin (mean 31%, median 24%) however the difference was not statistically significant. The bioavailability of cefuroxime axetil was low due to being administered in the fasting state. The relatively low penetration ratios of both drugs into samples of whole tissue can be explained by the localization of betalactam antibiotics primarily in the extracellular fluid, with low penetration into normal cells. Both drugs were found to reach concentrations in tonsil tissue above the minimum inhibitory concentration for Group A beta-haemolytic streptococci after a single oral dose. In addition to streptococci, Haemophilus influenzae and beta-lactamase producing Staphylococcus aureus were isolated in a significant number of the tonsils. These bacteria may play a pathogenic role, but this was not investigated.

The effect of peritonitis on the transperitoneal transport of cefuroxime in patients on CAPD treatment.

The pharmacokinetics and transperitoneal transport of cefuroxime were investigated in CAPD patients without peritonitis (n = 6), receiving 500 mg of the drug intravenously (i.v.) and intraperitoneally (i.p.) on separate occasions. CAPD patients with peritonitis were also investigated after i.p. administration of an initial dose of 500 mg cefuroxime followed by repeated doses of 250 mg. Routine hospital CAPD procedures and dwell-time schedules were followed during the study, and frequent blood and dialysate samples were collected. Cefuroxime was analysed by HPLC methods, and pharmacokinetic parameters were calculated. In the patients without peritonitis, the following pharmacokinetic parameters after i.v. and i.p. administration did not differ significantly (mean +/- SD): elimination half-life, 15.1 +/- 1.9 h; apparent volume of distribution 27.9 +/- 2.91; and total clearance, 21.5 +/- 1.2 ml/min. In contrast, the transperitoneal transport of cefuroxime differed significantly in the three studies. After i.v. administration the apparent transperitoneal clearance was low and time dependent, ranging from 4.2 +/- 1.2 to 1.4 +/- 0.4 ml/min. After i.p. administration the apparent transperitoneal clearance increased to 10.9 +/- 2.4 ml/min, whereas in the peritonitis patients a further increase to 21.5 +/- 3.5 ml/min was observed. In all patients we found cefuroxime concentrations in serum and dialysate, greatly exceeding MIC values of most pathogens involved in CAPD peritonitis and other systemic bacterial infections.

Long-term pharmacokinetics of thio-TEPA, TEPA and total alkylating activity following i.v. bolus administration of thio-TEPA in ovarian cancer patients.

The serum pharmacokinetics of unchanged thio-TEPA and the active metabolite TEPA and the urinary excretion of thio-TEPA, TEPA and total alkylating activity were studied after a single i.v. bolus injection of thio-TEPA in six ovarian cancer patients. TEPA was present in serum as of 5 min after drug administration, and its concentration rapidly reached a plateau in the range of 50-100 ng/ml. After about 3 h the serum concentration of TEPA exceeded that of thio-TEPA, and in five of the six patients the metabolite persisted longer than the parent drug in serum. AUCs of thio-TEPA and TEPA were 822 +/- 83 and 1,084 +/- 234 ng h/ml, respectively. The great interindividual variation encountered in the serum pharmacokinetics of TEPA may be of clinical importance and represents a further indication that pharmacokinetically guided dosing of thio-TEPA could be valuable. Urinary recoveries of both thio-TEPA and TEPA were low, together constituting less than 2% of the delivered dose. A substantial gap existed between this and the total urinary alkylating activity, which averaged 13% of the dose in terms of thio-TEPA equivalents. This gap strongly indicates the presence of other unknown metabolites.

Pharmacokinetics of verapamil and norverapamil in patients with hypertension: a comparison of oral conventional and sustained release formulations.

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.

Single and multiple dose pharmacokinetics of tenoxicam in the elderly.

Fourteen elderly subjects (10 women, 4 men) with a mean age of 81 (SD 6.7) years and in need of anti-inflammatory drug treatment were given a single dose of 20 mg tenoxicam. After a drug-free interval of 5 weeks, multiple dose treatment with 20 mg tenoxicam once daily for 56 days was initiated. The single and multiple dose kinetics of tenoxicam were investigated after HPLC determination of tenoxicam in the plasma. The elimination half-life of tenoxicam ranged from 44 to 132 h (mean 71.9 h) with no significant difference between the single and multiple dosage regimens. Tenoxicam reached maximum plasma concentrations after 1.4 and 1.1 h, with values of 3.6 and 15.5 micrograms.ml-1, for the single and multiple dosage regimen respectively. The corresponding trough values (24-h values) were 1.8 and 11.7 micrograms.ml-1. A mean accumulation ratio of 5.1 was calculated. The mean increase in the area under the plasma concentration time curves at steady-state was 21% more than predicted from the initial single dose. This deviation from linearity was considered to be of minor clinical significance. The kinetics of tenoxicam in elderly were similar to that published for young healthy volunteers.

Pharmacokinetics and tissue concentrations of ceftazidime in burn patients.

The pharmacokinetics and tissue concentrations of ceftazidime have been investigated in 8 patients with severe burns (20-80% of body surface area) undergoing skin transplantation 2 to 21 days after injury. Two prophylactic doses of ceftazidime were administered as 1 g i.v. bolus injections with an 8 h interval. Blood, urine, burn blister fluid and tissue were frequently sampled and drug concentrations were analyzed by HPLC. The kinetics of ceftazidime was the same after each dose. In these patients the pharmacokinetics of ceftazidime was greatly altered from that in other patients and there was much interindividual variation. The mean ceftazidime elimination half-life, apparent volume of distribution and total clearance were: 2.7 h, 30.91 (0.38 1.kg-1) and 139 ml.min-1, respectively. A linear correlation was found between creatinine clearance and the renal clearance of the ceftazidime, the mean values being 108 and 95 ml.min-1, respectively. No correlation was found between creatinine clearance and the total clearance of ceftazidime. The mean percentage urine recovery was 69% of the dose. Tissue and burn blister fluid concentrations were above the MIC, and ranged from 40.0 to 3.1 mg.kg-1. A substantial increase in the apparent volume of distribution and non-renal clearance of ceftazidime was observed, probably due to increased capillary permeability and drug loss through the wound surface replacement of prior to surgery and subsequently to lost and blood fluid.

Pharmacokinetics and distribution of diazepam and oxazepam in early pregnancy.

The transfer of drugs from the mother to the fetus is important from the view of possible harmful as well as therapeutic effects on both mother and fetus. In the first trimester of pregnancy this has been sparsely investigated. In 66 first-trimester pregnant women, who had applied for legal termination of the pregnancy, we have calculated different pharmacokinetic parameters of two benzodiazepine derivatives, diazepam and oxazepam, after administration of a single oral dose of 10 or 25 mg to the mother. The calculated pharmacokinetic parameters were within the normal range for healthy adults. The pharmacological active metabolite n-desmethyldiazepam was measured in concentrations near the detection limit. The penetration of diazepam and oxazepam from maternal serum to placental tissue in a 4 h period after drug administration was 31.5% and 49%, respectively, indicating a rapid transfer.

The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy.

We have studied the pharmacokinetics of ceftazidime in 37 patients suffering from serious bacterial infections. All the patients had impairment of renal function and received moderate to high doses of frusemide concurrently. The doses of ceftazidime were given according to renal function as recommended by the manufacturer. Serum and urine samples were frequently collected, and drug concentrations measured by high performance liquid chromatography. The patients were grouped and evaluated according to renal function, mean (SD) creatinine clearances ranging from 70.1 (12.4) to 11.0 (3.2) ml.min-1. The pharmacokinetics of ceftazidime depended on renal function. A statistically significant increase in ceftazidime elimination half-life and decreases in urinary recovery, total body clearance, and renal clearance in proportion to the decrease in renal function were observed (p less than 0.05). The apparent volume of distribution also increased, but not significantly (p greater than 0.05). A linear correlation was found between the total body and renal clearances of ceftazidime and creatinine clearance. The extrarenal clearance increased from 3.9 to 14.0 ml.min-1 with decreasing renal function. Concurrent treatment with ceftazidime and moderate to high doses of frusemide did not impair renal function and no evidence of nephrotoxicity was found.

Pharmacokinetics of thio-TEPA at two different doses.

Thio-TEPA pharmacokinetics were studied at doses of 20 mg and 30 mg in six patients treated for ovarian cancer. Considerable interindividual variation was encountered in its pharmacokinetics, which were dose-independent within the dose range studied and similar to those reported at far higher doses. Interindividual dosing of thio-TEPA based on an initial AUC estimation is suggested.

The penetration of ceftazidime into the inflamed rabbit eye.

Acute endophthalmitis was unilaterally induced in 8 rabbits by intravitreal injection of 5 micrograms Escherichia coli endotoxin. A reproducible increase in aqueous humour polymorphonuclear neutrophils and total protein content was observed after 24 h (mean +/- SD: 2400 +/- 274 X 10(6)/l and 3.7 +/- 0.4 g/l, respectively). In the opposite eye only minor changes occurred, making it suitable as a paired control. The intraocular penetration of ceftazidime was then studied in 30 rabbits after i.v. injection of 50 mg/kg body weight. The mean penetration into aqueous humour of the eyes with and without endophthalmitis was 64 and 10%, respectively. In the vitreous body the corresponding penetration was 5 and 1%. The concentration of ceftazidime achieved in the intraocular structures was sufficient to inhibit the growth of pathogens, i.e. Enterobacteriaceae, commonly responsible for intraocular infections.

Ofloxacin versus trimethoprim-sulphamethoxazole in acute cystitis.

The clinical and bacteriological efficacy and adverse reactions of ofloxacin vs trimethoprim-sulphamethoxazole were investigated in a double-blind, randomised study in 250 female patients (125 in each group) with acute, uncomplicated lower urinary tract infections. The dosages of ofloxacin and trimethoprim-sulphamethoxazole were 100mg and 160mg + 800mg twice daily, respectively. The duration of therapy was 3 days. 81% of the patients had significant bacteriuria. Escherichia coli was isolated in 76% and Staphylococcus saprophyticus in 11% of the infections. The bacteriological elimination, clinical cure and improvement rates of the evaluable patients on ofloxacin treatment were 92 and 95%, respectively. The corresponding figures on trimethoprim-sulphamethoxazole therapy were 88 and 90%. Adverse reactions were clinically unimportant, and none of the patients had to stop treatment. Mild and transient side effects, mainly from the gastrointestinal tract, central nervous system and skin, were reported by 19 and 22% of the patients in the ofloxacin and trimethoprim-sulphamethoxazole groups, respectively. None of the differences in clinical and bacteriological efficacy and side effects of ofloxacin vs trimethoprim-sulphamethoxazole were statistically significant. Ofloxacin appears to be an appropriate antibiotic for short term therapy of acute, uncomplicated, lower urinary tract infections, comparing favourably with trimethoprim-sulphamethoxazole treatment in this study.

Single and repeated dose pharmacokinetics of thio-TEPA in patients treated for ovarian carcinoma.

Triethylenethiophosphoramide (thio-TEPA) pharmacokinetics were studied in 15 patients being treated for epithelial ovarian carcinoma. Unchanged thio-TEPA was assayed in serum and urine by means of a gas chromatographic procedure. No accumulation or alteration of the pharmacokinetics occurred during therapy, which was continued for up to 7 months with biweekly administrations of 20 mg, after two initial loading courses with 20 mg daily for 3 consecutive days 2 weeks apart. No significant difference in the pharmacokinetics between i.m. and i.v. administration was demonstrated. However, three patients showed a reduced absorption ability from the i.m. injection site to the systemic circulation and an apparent increase in the elimination half-life (3.86 +/- 0.97 h), which could be of clinical relevance. A first-order elimination process with a short elimination half-life (approximately 1.5 h) was demonstrated for thio-TEPA in all patients after i.v. administration. The apparent volume of distribution averaged 50 1. The renal clearance was below 1% of the total-body clearance, which averaged 412 ml/min. The urinary excretion of unchanged thio-TEPA was complete within 8 h after administration, with an average urinary recovery of 0.14% of the dose. Calculation of the area under the serum concentration vs time curve revealed wide variation between patients (range 517-1480 ng/h ml-1), indicating the need for drug monitoring during therapy.