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Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

Probenecid with its phase-I metabolites, and phase-II glucuronide conjugate can be analysed by a gradient high pressure liquid chromatographic method. Probenecid glucuronide in plasma with pH 7.4 is not stable and declines to 10% of the original value within 6 h (t1/2 approximately 1 h). Probenecid glucuronide is stable in urine with pH 5.0, moderately unstable at pH 6.0 (t1/2 approximately 10 h), and unstable at pH 8.0 (t1/2 approximately 0.5 h). Probenecid glucuronide is stable in water and 0.01 mol/l phosphoric acid in the autosampler of the high pressure liquid chromatograph. The decrease in concentration in water is 5.5% during 9 h and 0% in diluted acid. Probenecid glucuronide and the phase-I metabolites were not detectable in plasma. The main compound in fresh urine is the phase-II conjugate probenecid glucuronide (62% of a 500 mg dose); the phase-I metabolites are present and only a trace of probenecid is present. The percentage of the dose of the phase-I metabolites varies between 5 and 10, while hardly any probenecid is excreted unchanged (0.33%).

Sulfamethomidine metabolism was studied in 6 volunteers. In humans, only N1-glucuronidation and N4-acetylation take place, leading to the final double conjugate N4-acetylsulfamethomidine N1-glucuronide. The N1-glucuronides were directly measured by high pressure liquid chromatography. Fast and slow acetylators show a similar half-life for sulfamethomidine (26 +/- 6 h) and its conjugates sulfamethomidine (26 +/- 6 h) and N4-acetylsulfamethomidine (36 +/- 16 h). Approximately 50-60% of the oral dose of sulfamethomidine is excreted in the urine, leaving 40-50% for excretion into bile and faeces. The main metabolite of sulfamethomidine is its N1-glucuronide, which accounts for 36 +/- 7% of the dose, followed by N4-acetylsulfamethomidine (16 +/- 8%). N1-glucuronidation results in a 75% decrease in protein binding of sulfamethomidine. N4-acetylsulfamethomidine and its N1-glucuronide showed the same high protein binding of 99%. The renal clearance of N4-acetylsulfamethomidine is 7.9 +/- 2.2 ml/min and approximately 20 times as high as that of the parent drug (0.46 +/- 0.16 ml/min). Total body clearance of sulfamethomidine is 4.5 +/- 0.9 ml/min and the volume of distribution in steady state 10.6 +/- 1.7 1. No measurable plasma concentrations of the N1-glucuronides from sulfamethomidine are found in plasma. This may be explained by renal glucuronidation after active tubular reabsorption.

In ten patients who received an epidural injection of 15 mg of nicomorphine, the compound was relatively slowly released from the epidural space and was found in plasma for approximately 1.5 h. Nicomorphine is relatively slowly metabolized into 6-nicotinoylmorphine and morphine. The rate of release is patient-dependent. The relative AUC values are 15.3% for nicomorphine, 23.9% for 6-nicotinoylmorphine and 60.8% for morphine. The mean clinical effect lasts for 18.2 +/- 10.1 h.

Three high pressure liquid chromatographic systems for the separation of oxazepam, temazepam and their glucuronides (system A), the separation of their R,S glucuronide diastereomers (system B) and the chiral separation of the parent drugs (system C) are described. Preliminary pharmacokinetics of R,S-oxazepam and R,S-temazepam in a human volunteer reveal that the protein binding of the glucuronides is lower than that of the parent drugs, but that there is no difference in protein binding between the R-oxazepam/temazepam and S-oxazepam/temazepam and their corresponding glucuronides. The S-glucuronide is the main metabolite formed and excreted by man. The plasma ratio R/S-glucuronide is 1:1 for both oxazepam and temazepam. The renal clearance of R-temazepam, and S-temazepam are similar, and those of R-oxazepam and S-oxazepam tend to be different.

To 6 pregnant patients with preterm premature rupture of the membranes, cefuroxime prophylaxis was given 1,500 mg three times daily intravenously. Cefuroxime concentrations were assayed in maternal plasma and amniotic fluid during pregnancy and in umbilical cord blood, placenta, and membranes after delivery. Our results showed a high rate of transplacental transfer of cefuroxime. Bactericidal levels could be demonstrated in maternal plasma, and in amniotic fluid leaking from the vagina. Therapeutically active levels were present in the newborns. The absorption of cefuroxime by the foetal membranes was high. Although the neonatal morbidity in this high-risk population was low, the data are still too preliminary to advise the routine prophylactic use of cefuroxime to pregnant patients with preterm premature rupture of the membranes.

Cefuroxime is well-absorbed and distributed over the human body. This review gives a general summary of published information on tissue concentrations of cefuroxime after an intravenous or intramuscular dose of 750 or 1,500 mg of cefuroxime. Tissue concentrations are given for blister fluid, meninges, eyes, respiratory tract, sputum and bronchi, abdominal and urogenital tract, uterine, ovarian and fallopian tube tissue, myometrium, membranes, placenta, puruloid and healthy human milk, bile, prostate, hip and knee bone. Pharmacokinetics are reviewed in patients with impaired kidney function and in pregnancy.

A direct high pressure liquid chromatographic analysis of sulfaphenazole-N2-glucuronide in urine is described. After an oral dose of 439 mg of sulfaphenazole, 0% is excreted unchanged in the urine, less than 1% is excreted as N4-acetylsulfaphenazole. As N2-glucuronide 49.4% is excreted in one slow acetylator and 84.8% in one fast acetylator.

The bioavailability of two prazosin formulations was studied in 12 healthy volunteers. 1 Subject left the study. Based on the statistical tests of the pharmacokinetic parameters of prazosin in 11 volunteers, such as t 1/2, Cmax, tmax and AUC, it could be concluded that both preparations had comparable bioavailabilities.

Sulfadimethoxine is metabolized by O-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8 +/- 4.2 h versus 36.3 +/- 5.4 h; P = 0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3 +/- 5.2 h versus 53.5 +/- 8.5 h, P = 0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50-60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40-50% for excretion into bile and faeces.

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30-80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (+/- 0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml.min-1 (+/- 44), plasma protein binding 35% (+/- 6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (+/- 16). Its apparent renal equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.

Nalidixic acid is metabolized by hydroxylation to 7-hydroxymethylnalidixic acid[[ and then by oxidation to 7-carboxynalidixic acid.[[ The half-lives of the two elimination phases of nalidixic acid are 0.75 and 2.5 h. The apparent half-lives of the metabolite 7-hydroxymethylnalidixic acid are 2.5 and 5.5 h. Plasma protein binding of nalidixic acid is 95% and that of 7-hydroxymethylnalidixic acid 65%. The renal clearance of nalidixic acid varies between 2 and 25 ml/min and that of 7-hydroxymethylnalidixic acid between 37 and 162 ml/min. Of nalidixic acid 42% is glucuronidated and 40% hydroxylated. Of the hydroxy metabolite 57% is glucuronidated and 32% excreted unchanged. 7-Carboxynalidixic acid is excreted in the urine and is not glucuronidated. The variations in the glucuronidation/hydroxylation ratio of nalidixic acid and the glucuronidation/renal excretion ratio of the 7-hydroxymethyl metabolite belong to a normal distribution.

Pharmacokinetic parameters of the bronchodilator theophylline were assessed in eight patients with chronic obstructive lung disease when administered alone and when comedicated with ciprofloxacin 500 mg twice daily, ofloxacin 400 mg twice daily, or pefloxacin 400 mg twice daily. Compared to the control period, in which only theophylline was administered, the total body clearance of theophylline decreased significantly during ciprofloxacin (30.4%) and pefloxacin (29.4%) coadministration, whereas no change of the renal clearance of theophylline occurred. Ofloxacin did not influence the pharmacokinetic parameters of theophylline. From these observations it is concluded that ciprofloxacin and pefloxacin reduce the metabolic clearance of theophylline.

The effects of altered albumin distribution on the apparent volume of distribution (V) and the apparent elimination rate constant (kappa) of drugs were investigated by a simulation analysis. The Equations derived by Oie et al. were modified for this purpose. Within the range observed in normal healthy subjects and patients, the change in albumin distribution significantly affected V of drugs but, in general, not kappa. For drugs with more than 90% plasma-protein binding, V changed by more than 100%. The change in plasma-protein binding caused by an altered albumin distribution produced a greater effect on V than that caused by an altered albumin amount. These results suggest that albumin distribution is an important factor in controlling the kinetics of drugs which are highly bound to plasma protein. This is illustrated using midazolam as an example.

The quinolones are relatively poorly absorbed from the gastrointestinal tract. The elimination proceeds mainly by renal excretion. The half-life of elimination depends on the molecular structure and varies between 2 and 10 h. Impaired kidney function is expected to increase the half-life of elimination, though this effect is not always observed. Since the 4-oxo-metabolites show a higher renal clearance than the parent drug, renal impairment will result in a cumulation of the metabolites in the body.

For the following compounds: sulfamerazine, 4- hydroxysulfamerazine , N4- acetylsulfamerazine , N4-acetyl-4- hydroxysulfamerazine , the following data are reported: biosynthesis in the dog, isolation, identification by MS and NMR, TLC (Rf values) and HPLC (capacity factors and molar extinction), half-life of elimination, metabolism, renal excretion and protein binding in dog. Dogs are unable to acetylate sulfamerazine, but eliminate predominantly by hydroxylation of the N1-substituent. Administered N4- acetylsulfamerazine is predominantly eliminated by deacetylation to sulfamerazine which in turn is hydroxylated. The renal clearances of sulfamerazine and N4- acetylsulfamerazine in the dog are identical. The renal excretion of both compounds proceeds by the passive processes of glomerular filtration and tubular reabsorption. 4- Hydroxysulfamerazine and its glucuronide have a higher renal clearance than sulfamerazine.

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite were studied in a patient undergoing continuous ambulatory peritoneal dialysis. A biphasic plasma-disappearance pattern of methotrexate was observed, with half-lives of 3.5 and 29 hours. The 7-hydroxy metabolite accumulated and showed a very slow rate of elimination, with an estimated final elimination half-life of over 120 hours. The mean peritoneal clearance rate of methotrexate was 0.13 l/h (range 0.05-0.20 l/h), dwell times significantly influenced the clearance rate. Strict monitoring of the methotrexate level, even after low doses, is necessary in continuous ambulatory peritoneal dialysis patients, to prevent serious bone marrow toxicity.

In oncochemotherapy with methotrexate (MTX) a peripheral concentration greater than 0.45 mg/l and a plasma concentration less than 45 mg/l must be maintained for 20 h. The time periods required to reach and maintain steady-state concentrations after tapered and linear intravenous infusion were compared. Pharmacokinetic analyses according to a two-compartment model were used to calculate dosage regimens and concentration profiles by means of the Bayesian General Modelling Program (BM) and NONLIN. When the dosage regimen is based on a steady-state concentration in the peripheral compartment (which is the target compartment for MTX) tapered infusion reaches this concentration 40% faster and maintains it 12.5% longer, but no difference is found if the dosage regimen is based on a steady-state concentration in the central compartment. In theory the two-step 24-hour tapered infusion can be replaced by a bolus injection plus linear infusion in the ratio 1:2 of the total dose. These dosage regimens are to be preferred over linear infusion.

The tick-borne fever (TBF) model was used to study the effect of fever on the metabolism of sulfadimidine in goats. During TBF the elimination half-lives were prolonged, and the renal clearance values of sulfadimidine and the majority of its metabolites were markedly diminished compared with those in the uninfected state. During TBF the steady-state levels of the hydroxy metabolites were markedly increased. TBF reduced the extent of hydroxymethylation of the pyrimidine side chain; TBF did not affect acetylation of sulfadimidine. In one goat a progressive accumulation of the metabolites was noticed.

Cefradine and co-trimoxazole pharmacokinetics were studied in a patient with peritonitis that complicated continuous ambulatory peritoneal dialysis (CAPD). Concentrations in the plasma reached after oral administration of 500 mg cefradine four times daily and 400/80 mg co-trimoxazole four times daily were for cefradine 100 micrograms/ml, for trimethoprim 15 micrograms/ml, and for sulfamethoxazole 100 micrograms/ml, respectively. In the dialysate concentrations were reached of 35-70 micrograms/ml cefradine, 2-5 micrograms/ml trimethoprim and 8-17 micrograms/ml sulfamethoxazole. The values for sulfamethoxazole are regarded too low to be clinically effective. Half-lives, protein binding values and CAPD clearances are presented. Low CAPD clearances were obtained during the night and high values during the day. The dosage yielded too high plasma trimethoprim concentrations, while sulfamethoxazole dialysate concentrations were too low. It seems questionable therefore whether co-trimoxazole can be used orally for the treatment of CAPD peritonitis.

In patients treated concomitantly with theophylline and enoxacin, a broad spectrum antibacterial agent for oral administration, unexpectedly high plasma theophylline concentrations were observed. In six patients receiving intravenous aminophylline under controlled conditions, enoxacin was started in a daily dose of 800 or 1200 mg. Plasma theophylline concentrations increased from 8.4 +/- 2.4 mg/l to 15.0 +/- 5.1 mg/l at day 3 of co-administration. Total body clearance of theophylline decreased significantly, whereas renal clearance and protein binding did not change. When enoxacin, 800 mg daily, was administered to seven patients with a stable chronic obstructive pulmonary disease, who were on long-term theophylline treatment a significant increase in plasma theophylline concentrations occurred as well: elimination half-life was prolonged. It is concluded that the rise of plasma theophylline concentrations is caused by a reduced metabolic clearance of theophylline. If concomitant use of both drugs is necessary, monitoring of plasma theophylline concentration and adjustment of the theophylline dose is recommended, to avoid toxicity.

Sulfadiazine, sulfamerazine, sulfadimidine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation, protein binding, half-lives of elimination and apparent and true renal clearance values were measured. Methyl substitution in the N1-pyrimidine ring favours acetylation by an additional N-acetyltransferase isoenzyme present in 'fast' acetylators only. Methyl substitution in the N1-pyrimidine ring favours renal clearance of the N4-acetylsulfonamide derivatives. The N1-substituent probably reinforces the binding of the N4-acetyl group to the active tubular transport mechanism. The renal clearance of these sulfonamides is not dependent on the structure of the N1-substituent.

High doses of co-trimoxazole in a patient with Pneumocystis carinii and impaired kidney function (creatinine clearance 10 ml/min) resulted in a declining renal clearance of the drug but did not affect the average creatinine clearance. The renal clearance of sulfamethoxazole and its metabolites 5-hydroxy-, N4-acetyl-, N4-acetyl-5-hydroxysulfamethoxazole decreased 80%, while the renal clearance of trimethoprim decreased 60%. The renal clearance of all compounds was evidently dependent on urine flow. The observed phenomena may be explained by the assumption that crystalluria occurred, obstructing kidney tubules. The crystalluria effect can be reversed by cessation of the drug or by lowering its dosage.

The pharmacokinetic parameters of theophylline and its major metabolites were measured in two healthy volunteers, after the administration of theophylline alone and during co-medication with ofloxacin, 200 mg twice daily, or enoxacin, 200 mg twice daily. During enoxacin co-medication, elimination half-lives of theophylline increased from 8.7 h to 17.4 h and from 6.1 to 12.3 h, respectively. As the renal clearance of theophylline did not change, the decreased elimination of theophylline during enoxacin co-medication must result from a reduced metabolic clearance. Enoxacin co-medication caused a clearly decreased formation of the metabolites 1-methyluric acid and 3-methylxanthine, formed by N-demethylation, whereas the C-8 oxidation of theophylline was less influenced compared to the blank. Enoxacin's interference with the theophylline disposition is predominantly based on the inhibition of the microsomal N-demethylation. Ofloxacin co-medication did not induce a change in the plasma parameters or renal excretion of theophylline and its metabolites.

The use of vancomycin is rapidly increasing due to the emergence of strains of staphylococci resistant to betalactam antibiotics. In this communication the pharmacokinetics of an overdose of vancomycin in a patient during continuous ambulatory peritoneal dialysis (CAPD) is reported. Brainstem auditory evoked potentials (BAEPs) are used to assess ototoxicity. It could be shown that by shortening the dwell time, the apparent CAPD flow was increased and the vancomycin clearance was also increased. This may explain in part the differences in the values of vancomycin t1/2 in this patient (21 h) as compared to other studies (60-120 h). The age of the patient (3.5 years) may also have influenced the t1/2. Using brainstem auditory evoked potentials as a parameter to assess ototoxicity, it was shown that this patient suffered no damage from the overdose.

The pharmacokinetics of ciprofloxacin after a single intravenous administration of 100 mg were studied in intensive care patients with an acute renal impairment. There was no correlation found between the creatinine clearance and the renal clearance of ciprofloxacin. This applies to the entire group of patients. The decrease in renal clearance of ciprofloxacin was, however, more pronounced than the change in the elimination half-life, suggesting an important extra-renal elimination of the drug.

Articainic acid, a major metabolite of articaine, was administered to a volunteer. Since the renewed interest in the utilization of articaine in epidural anaesthesia, it has been important to assess the clinical effects of this metabolite. It was noted that articainic acid had no effect on EEG, ECG, blood pressure and heart rate. Pharmacokinetic parameters are given.

A pharmacokinetic study after a single dose of ceftriaxone, cefoxitin, cefuroxime and ceftazidime was performed to investigate the influence of protein binding and severity of disease on the renal elimination. In intensive-care patients drug-protein binding was substantially less compared to that in volunteers and patients with less complicated diseases. This did not result in increased elimination but, due to increased apparent volumes of distribution, prolonged half-life times were observed. Consequently, in patients with complicated disease states a dosage regimen should be based on pharmacokinetic studies performed in a similar patient group.

Sulfisomidine, sulfamethomidine, sulfadimethoxine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation and those of protein binding, the half-lives of elimination and the apparent and true renal clearance values were measured. No acetylation phenotype could be demonstrated in these compounds. Methoxy substitution in the NI-pyrimidine group of sulfisomidine affects predominantly the renal clearance value and mechanism of the parent compound but has no influence on the renal clearance of the N4-acetyl derivatives. The renal clearance value of sulfisomidine is 232 +/- 33 ml/min, of sulfamethomidine 21.60 +/- 16.4 ml/min and of sulfadimethoxine 10.87 +/- 10.44 ml/min. The renal clearance values of the corresponding N4-acetylsulfonamide derivatives are 314 +/- 91 ml/min, 342 +/- 63 ml/min and 202 +/- 65 ml/min respectively. Tubular reabsorption, caused by methoxy substitution in the NI-pyrimidine ring, lowers the rate of elimination and increases the half-life. The half-life of sulfisomidine is 8.5 +/- 0.5 h, of sulfamethomidine 27.8 +/- 5.3 h and of sufadimethoxine 34.6 +/- 10.4 h.

Although pancuronium has fewest side effects compared to other currently used non-depolarizing muscle relaxants, it is still not the ideal relaxant. Its structural analogues have been studied to derive such an ideal relaxant. Org-NC45 meets the requirements for such a relaxant best and is therefore extensively studied. It is more potent than pancuronium, has a shorter onset and duration of action and is free from cardiovascular side effects. Histamine release could not be demonstrated. It can be easily reversed by neostigmine, pyridostigmine or 4-aminopyridine. Interaction with antibiotics and anaesthetic drugs is not different from that of pancuronium.