Placental transfer and tissue distribution of vitamin E in pregnant rabbits.

alpha-Tocopherol (vitamin E) is widely prescribed in neonatal intensive care units, in large doses and by different schedules, for the prevention of retrolental fibroplasia, intraventricular haemorrhage, bronchopulmonary dysplasia, and haemolytic anaemia. Since the efficacy of the drug in premature newborns seems related to early administration, the physicochemical characteristics of the drug itself and available formulations limit the major therapeutic aim of promptly raising levels of vitamin E in premature babies during the early hours of life. It has thus been suggested that vitamin E be given to the mother before delivery to produce higher drug concentrations in the newborn. To see whether this would work, the tissue distribution and transplacental transfer of vitamin E were studied in six pregnant rabbits at steady-state after an i.v. bolus + infusion to give a mean venous blood concentration of about 325 mumol l-1 of alpha-tocopherol acetate, corresponding to about 30 mumol l-1 of alpha-tocopherol. Endogenous levels were measured in six control pregnant rabbits. In treated animals alpha-tocopherol was increased in liver, spleen, placenta, lung, mammary gland, blood, and bile but not in brain, heart, fat, muscle or adrenals probably because distribution into these tissues is very slow. Vitamin E levels in the placenta of treated mothers were 15 times those of control rabbits, but the vitamin was not detectable in amniotic fluid and only very low levels were found in fetal blood. These findings do not indicate any advantage of giving mothers alpha-tocopherol acetate before delivery.

In vivo and perfused liver caffeine kinetics in the rat.

The kinetics of caffeine (1,3,7-TMX) was investigated in male rats given four different doses (1, 2.5, 10 and 25 mg/kg), comparing the patterns found in vivo and after liver perfusion. The same animals were used in both experimental conditions in order to reduce the variability of the caffeine profile. For doses less than 10 mg/kg or mg/L, caffeine blood or perfusate concentrations/time profiles followed first-order kinetics and the elimination rate constant (average 0.013 min-1) and half-life (55 min) were similar for the in vivo and ex vivo conditions. After larger doses (10 and 25 mg/kg or mg/L), kinetics were nonlinear. The area under the blood or medium concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were observed, with significant differences for t 1/2 and CL after 10 and 25 mg/kg or mg/L, due to dose-dependent elimination of caffeine at these doses (Km of 8.3 and 7.8 micrograms/ml in vivo and in vitro, respectively). The two different approaches gave close kinetic estimates in vivo and in vitro. Thus, under standardized conditions, the isolated perfused liver technique is a useful tool for studying the kinetics of drugs eliminated by hepatic metabolism.

Pharmacokinetics of intraperitoneal teicoplanin in patients with chronic renal failure on continuous ambulatory peritoneal dialysis.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, is described in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). A single 3 mg kg-1 dose was given intraperitoneally in the dialysate during a 6 h dwell time. The drug appeared in the plasma within 15 min at 1.00-0.28 mg l-1 (mean +/- s.d. = 0.70 +/- 0.45) in all five subjects, and peak serum concentrations ranged from 5.53 to 2.80 mg l-1 (4.84 +/- 1.43) at 6 h. Approximately 70% (71 +/- 12) of teicoplanin was absorbed from the peritoneal dialysis fluid during a single 6 h dwell time. The rate constant for peritoneal transfer (lambda d) averaged 0.318 h-1 and the half-life (t1/2 lambda d) was 2.18 h. Further values were serum elimination half-life 114-173 h; total body clearance 263-532 ml h-1; steady-state volume of distribution 68-93 l. This drug profile closely agrees with data reported after intravenous injection in patients on CAPD and suggests that teicoplanin has bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid is consistently low. Instillation of teicoplanin in CAPD fluid may be a useful route of administration for treatment of peritonitis and exit site infections in CAPD patients.

Pharmacokinetics of a single intravenous dose of teicoplanin in subjects with various degrees of renal impairment.

The pharmacokinetic profile of teicoplanin after single 3 mg/kg doses in adults with different degrees of renal failure was reviewed. The disposition of teicoplanin was adequately described by a three-compartment open pharmacokinetic model and it appears to be primarily related to the degree of renal function. Teicoplanin total body clearance was less and the terminal elimination half-life progressively prolonged in association with renal failure, but the volume of distribution at steady-state did not change. Highly significant relationships between teicoplanin total body and renal clearance and creatinine clearance have been reported and serve as a basis for adjusting dosage in patients with renal failure. In patients on continuous ambulatory peritoneal dialysis teicoplanin, administered either intravenously or intraperitoneally, showed bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid was consistently low. Haemodialysis made no significant contribution to total body clearance of teicoplanin. Guidelines for administration of teicoplanin in patients with renal failure are discussed.

Teicoplanin pharmacokinetics in patients with chronic renal failure.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.

Pharmacokinetic and pharmacodynamic modelling of atenolol in rabbits maintained on continuous peritoneal dialysis.

The pharmacokinetic and pharmacodynamic profiles of atenolol were studied in adult male rabbits on continuous peritoneal dialysis given 3 mg/kg i.v. before and during renal failure. The average terminal elimination half-life for the drug was 2.5 h calculated from blood, dialysate or urinary data. This value increased about nine times in anuric conditions. Although atenolol was eliminated in the peritoneal fluid, the amount excreted was relatively low both in normal conditions and renal failure, respectively 0.6 and 7% of the administered dose. The pharmacokinetic model was extended by an "effect compartment", which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in atenolol blood concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean equilibration half-time of atenolol effect and blood concentrations was 0.7 and 1.5 h in normal and pathological states, respectively. The mean blood concentration required to produce 50% of heart rate fall was similar in both conditions, 0.23 mg/l. The nine-fold decrease of atenolol elimination in anuria was in good agreement with the increase in duration of the drug's effect, and was suitably described by the "effect model".

Experimental model for pharmacokinetic studies during continuous peritoneal dialysis in the rabbit.

An experimental model permitting continuous peritoneal dialysis in rabbits, very close to continuous ambulatory peritoneal dialysis (CAPD) as performed in humans, is described. Animals were carefully monitored before and during dialysis for plasma, urine, and dialysate biochemical parameters, and electrocardiogram, body temperature, weight, and white cell count in dialysate. Dialysis was performed successfully for 21 days without failure. Difficulties in setting up the final model are reported. The suitability of the model for pharmacokinetic and pharmacodynamic studies was borne out by administering atenolol (i.v. before CADP, i.v. after one week of CAPD, and i.p. one week later) and analyzing the findings.

Pharmacokinetics of teicoplanin in patients on continuous ambulatory peritoneal dialysis.

We have studied the pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). Although teicoplanin was eliminated in the peritoneal fluid, relatively little was recovered (6.8 +/- 1.2% of the given dose). The following values were obtained: elimination half-time 102-347 h; total body clearance 4.16-7.38 ml X h-1 X kg-1, peritoneal clearance 0.31-0.37 ml X h-1 X kg-1. Because the elimination of teicoplanin is about four times less in patients undergoing CAPD compared with subjects with normal renal function, the dose of teicoplanin should be reduced appropriately in such cases.

Pharmacokinetics of theophylline and its metabolites in rabbits.

The pharmacokinetics of theophylline (1,3-DMX) and its metabolites were investigated in detail in four male rabbits after bolus intravenous injection (12 mg/kg) of the compound. Theophylline was measured in blood and urine, and its metabolites were determined only in urine. Apparent first-order rate constants for the metabolic processes involved in the formation of 1,3-DMX metabolites and their excretion in urine were calculated. An appropriate 13-compartment model was formulated to describe the disposition of 1,3-DMX and its metabolites.

Pharmacokinetics of theobromine and its metabolites in rabbits.

The pharmacokinetics of theobromine (3, 7-DMX) and its metabolites was investigated in detail in four male rabbits after bolus intravenous injection (4 mg/kg) of the compound. Apparent first-order rate constants for the metabolic processes involved in the formation of 3,7-DMX metabolites and their excretion in urine were calculated. Theobromine, 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX) were measured in blood and urine, and the other metabolites were determined only in urine. An appropriate model of 14 compartments is formulated to describe the disposition of 3,7-DMX and its metabolites.

Pharmacokinetics of teicoplanin in man after intravenous administration.

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3-mg/kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 micrograms/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the lambda 1 phase was 20.3 min, that of the lambda 2 phase was 2.9 hr, and the half-life of the estimated lambda 3 phase was 40.5 hr, in good agreement with that of the lambda z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 micrograms/ml) on many pathogenic organisms for at least 1 day after administration.

Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits.

The kinetics and metabolism of theobromine (3,7- DMX ) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7- DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7- DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7- DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7- DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7- DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.