Kinetics of atrial natriuretic peptide in young and elderly subjects.

To study the influence of age on the kinetics of atrial natriuretic peptide (ANP) in man, human (99-126) ANP 2.0 micrograms.min-1 was infused IV for 60 min in 8 healthy young (18 to 25 y) and 9 healthy elderly (71 to 84 y) subjects. Both baseline ANP values and the levels at the end of infusion were higher in the elderly subjects. The mean residence time of ANP in the two age groups was not significantly different, whereas total body clearance (CL) was markedly diminished in the elderly as compared to the young subjects (mean +/- SD 3.1 +/- 1.0 l.min-1 and 6.2 +/- 4.1 l.min-1, respectively). The apparent volume of distribution at steady state was lower in the elderly than in the young, but the difference was not significant (mean +/- SD 44 +/- 19 and 103 +/- 111, respectively. The decrease in CL largely explained the higher ANP levels found in the elderly subjects. The MRT and the plasma half-life of the terminal phase did not differ between the two groups. In the elderly but not in the young subjects the calculated endogenous creatinine clearance was closely correlated with the CL (r = 0.90, P less than 0.001), thereby emphasizing the importance of the kidney in the metabolic clearance of ANP in the elderly.

Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients.

The pharmacokinetic parameters of 16 patients in the intensive care unit, sedated with midazolam, were evaluated. A large variation was observed in the plasma concentration of midazolam and between the plasma concentration of midazolam and its metabolite 1-hydroxymethylmidazolam glucuronide. The plasma albumin concentration governs the volume of distribution of midazolam. Decreased plasma albumin concentration (25 gm/L) results in an increased volume of distribution and a decreased elimination rate of midazolam. The observed plasma concentration ratio between the parent drug and its metabolite 1-hydroxymethylmidazolam glucuronide is governed by the variables of protein binding, the metabolic rate of midazolam, and the renal clearance of the glucuronide metabolite itself (which can be considered as a measure of the kidney function of the patient).

Plasma and urinary excretion kinetics of oral baclofen in healthy subjects.

Baclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured. After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14)%. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data. The renal excretion rate constant had the high mean value of 0.35 (0.24) h-1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH. Although active tubular secretion may contribute to its renal clearance, as shown by the effect of co-administration of probenecid, glomerular filtration appears to be the dominant transport mechanism.

In vivo and in vitro pharmacokinetic differences between four structurally closely related anthracyclines in hematopoietic cell subtypes in humans.

Minor differences in chemical structure of adriamycin (ADM), 4'-epiadriamycin (E-ADM), daunomycin (DNM), and 4-demethoxydaunomycin (D-DNM) lead to large differences between cellular and plasma pharmacokinetic parameters in vivo, as well as in cellular drug handling. Anthracyclines accumulated in cells to several hundred-fold the plasma concentration. Half-lives, as well as the ratio of parent drug/metabolite, differed markedly. The slopes of the in vivo cellular concentration-time curves after the end of the bolus injection resembled the efflux curves observed after a 5-min exposure in vitro. In vivo, the area under the cellular concentration-time curve (AUCc) for equimolar dosages was largest for ADM and smallest for D-DNM. In vitro however, cellular drug levels and AUCc were highest for D-DNM, followed by DNM, E-ADM, and ADM. Final cellular drug concentrations were 300-2500 times the medium concentration, with clearly higher values observed after the 360-min exposure. Minor structural differences were related to considerable variations in cellular drug handling, with different patterns in vivo and in vitro. These studies point to difficulties occurring in the in vitro experimental studies of in vivo pharmacokinetic properties of anthracyclines and stress the need for direct determination of target cell drug concentrations in vivo, in the search for the understanding of cell drug handling-related mechanisms of action of the anthracyclines.

Pharmacokinetics, metabolism, and renal excretion of articaine and its metabolite articainic acid in patients after epidural administration.

Articaine is metabolized into articainic acid. The half-lives of articaine are 0.54 +/- 0.05 and 2.44 +/- 0.30 h and that of its metabolite, 2.44 +/- 0.30 h. Of the administered dose approximately 2-5% is excreted unchanged, 40-70% is excreted as articainic acid, and 4-15% as articainic acid glucoronide. The percentage of the total dose recovered in the urine varies between 50% and 91%. Protein binding of articaine in patients varies between 50% and 70%, and that of articainic acid between 60% and 90%. Renal clearance of articaine varies between 12 and 28 ml min-1, while that of articainic acid is between 84 and 160 ml min-1.

Comparison of the pharmacokinetics of intravenously administered rac-baclofen and its (-)-(R)- and (+)-(S)-enantiomers in dogs.

Baclofen is a centrally acting muscle relaxant marketed as the racemate. Since only the (-)-(R)-enantiomer is pharmacologically active, the pharmacokinetics of rac-baclofen and its enantiomers were studied individually in the same group of dogs to determine if there was any stereospecificity in the drug's kinetics after a single intravenous dose. High-pressure liquid chromatography was used to determine concentrations in plasma and urine. A major difference was found in the urinary recovery of the unchanged drug. Only about 50% of the dose of the clinically used racemate appeared as unchanged drug in the urine; whereas the active (-)-(R)-isomer was for the most part renally excreted (85%). Irrespective of isomeric composition, the renal clearance was dependent upon the creatinine clearance. Differences in non-renal clearance could not be explained by stereoselective formation of the gamma-hydroxymetabolite. It is concluded that in the dog, the active enantiomer is also pharmacokinetically preferred.

Clinical effects and pharmacokinetics of articainic acid in one volunteer after intravenous administration.

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.

Deterioration of kidney function by high doses of co-trimoxazole in man.

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.

Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5-hydroxy- and N4-acetyl-metabolites in man.

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.

Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose.

In five cases of carbamazepine (CBZ) intoxication, the time curves of the plasma concentration and of the renal excretion rate of carbamazepine and its metabolites carbamazepine 10,11-epoxide (CBZ-epoxide) and trans-10,11-dihydro-10,11-dihydroxy-CBZ (CBZ-diol) were measured. Pseudo-steady-state or plateau-like plasma concentration-time curves were observed when doses of 12 or 18 g of CBZ were ingested. Hemoperfusion lowers the plasma concentration of CBZ and its metabolites by affecting the half-life. The effect of hemoperfusion is reduced by the continuous absorption from the gastrointestinal tract and redistribution from the tissues. The renal clearances of CBZ and of CBZ-epoxide are low (1 and 8 ml/min, respectively); both are flow dependent. The renal clearance of CBZ-diol is approximately 160-350 ml/min and is independent of the urine flow. Although urine stimulation increases the renal clearance of CBZ by 100%, the overall amount excreted increases only 1-2% of the dose. Protein binding of CBZ is approximately 80%, of CBZ-epoxide 50%, and of CBZ-diol 70%.

Comparison of linear and tapered intravenous infusion of methotrexate in oncochemotherapy. A theoretical approach.

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.

Some pitfalls in selecting descriptive pharmacokinetic models.

Some pitfalls in selecting pharmacokinetic models are enumerated. To calculate the pharmacokinetic parameters of a drug that exhibits a biphasic convex plasma concentration-time curve, a two-compartment model does not automatically have to be applied. When only the parent drug in plasma is considered, a two-compartment model seems to be most appropriate. However, when the kinetic behavior of the metabolite has to be taken into account, and when a metabolic equilibrium underlies the metabolic elimination, the two-compartment model may not be appropriate. Also, when calculating the kinetic parameters of a drug with a concave biphasic plasma concentration-time curve, a capacity-limited metabolic conversion is not the automatic explanation for this observation. Limitations in renal excretion and bioavailability may be the reasons for this behavior. Convex and concave biphasic plasma concentration-time curves are illustrated, using sulfonamides as test compounds.

Effects of methoxy groups in the NI-substituent of sulfonamides on the pathways of elimination in man. The acetylation-deacetylation equilibrium and mechanisms of renal excretion of sulfisomidine, sulfamethomidine and sulfadimethoxine.

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.

The effect of the molecular structure of closely related N1-substituents of sulfonamides on the pathways of elimination in man. The acetylation-deacetylation equilibrium and renal clearance related to the structure of sulfadiazine, sulfamerazine and sulfadimidine.

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.

Change in transfer rate of methotrexate from spinal fluid to plasma during intrathecal therapy in children and adults.

Methotrexate plasma concentrations were measured repeatedly over 48 hours after each of 5 subsequent intrathecal injections in 14 children and 8 adult patients with acute lymphoblastic leukaemia. Two patterns of concentration profiles were distinguished: a) The plasma concentration reached a rather low maximum, followed by a relatively slow decline ('slow type'): b) The plasma concentration increased rapidly to a relatively high value after which it declined rather steeply ('fast type'). The incidence of the 'fast type' increased progressively with the number of intrathecal injections. When the plasma concentration-time curves were described by a pharmacokinetic 2-compartment open model with first-order absorption, it was calculated that the transfer of methotrexate from the spinal fluid into the plasma is much slower for the 'slow type' compared with the 'fast type'. Assuming concentration-dependent cytostatic activity, the therapeutic efficacy in the central nervous system is likely to be less for the 'fast type' than for the 'slow type'. Systemic toxicity resulting from the 'slow type' is expected to be higher than from the 'fast type'.