Concomitant cyclosporin and ketoconazole.
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Cyclosporins↗
Biomedical subjects
F J Frey
Publications and source records attributed to F J Frey.
Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function.
A single intravenous and oral dose of moclobemide (Ro 11-1163) was administered to 13 subjects with varying degrees of renal impairment (creatinine clearances ranging from 0 to 40 mL/min). The resulting disposition and absorption parameters of moclobemide were more variable than but, with the exception of mean absorption time, were not significantly different from values obtained in another study conducted in 12 normal healthy subjects. There were no relationships between any of the disposition parameters and renal function as measured by creatinine clearance. The disposition of two metabolites of moclobemide were partially characterized from plasma data. One of these (Ro 12-8095) appears to be formation rate-limited and, from available data, behaves in a manner similar to what has been observed in normals. The other metabolite (Ro 12-5637) has a long apparent disposition half-life and is present in greater concentrations in the renally impaired compared to the normal subjects. The latter observation may reflect reduced elimination clearance in the renally impaired subjects. Based upon the results of this study there does not appear to be any need to alter the normal dosing regimen of moclobemide in subjects with renal impairment in order to achieve drug concentrations similar to those in healthy subjects.
Administration, Oral↗
Pharmacokinetics and chronic toxicity of cyclosporine A in genetic hydroxylation-deficient dark Agouti rats.
Since oxidation plays a key role in the metabolism of cyclosporine A (CsA), the pharmacokinetics and the toxicity of CsA was investigated in female dark Agouti rats exhibiting a deficiency for debrisoquine hydroxylation and for dextromethorphan demethylation. When compared with Wistar rats (n = 10), dark Agouti rats (n = 10) had a higher mean clearance (4.8 ml/min per kg vs. 3.3 ml/min per kg) and a lower mean residence time (606 min vs. 1361 min) after intravenous dosing of CsA. The systemic availability of subcutaneous CsA was close to 100%. The steady state CsA concentrations assessed by HPLC in whole blood after subcutaneous dosing of 20 mg/kg per day for 23 days (n = 10) were about 1000 ng/ml in dark Agouti rats. When compared with dark Agouti rats treated with cremophore (n = 10) or not treated at all (n = 12), dark Agouti rats on chronic subcutaneous CsA plus cremophore for 23 days (n = 10) had no difference in kidney histology but had slightly increased liver fatty changes. Rats on CsA and/or cremophore had a decreased uric acid clearance and evidence of hypoaldosteronism. The urinary ratio of debrisoquine/4-hydroxydebrisoquine decreased in rats on CsA, whereas the O-demethylation and N-demethylation of liver obtained from rats on cremophore was impaired. Thus, dark Agouti rats show no difference in the metabolism of CsA and when given CsA for 23 days show drug-induced functional but no relevant structural light microscopic changes in the kidney, and functional and slight structural changes in the liver.
Animals↗
Preservation of body composition in renal transplant patients by cyclosporine, as opposed to prednisone.
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Adult↗
Clinical pharmacokinetics of prednisone and prednisolone.
The growth of knowledge in the field of the pharmacokinetics of prednisolone/prednisone has been slow for several reasons. First, convenient and specific methods for measuring these steroids only became available with the development of high performance liquid chromatographic methods. Secondly, prednisolone is nonlinearly bound to transcortin and albumin: since the unbound concentrations of prednisolone are biologically relevant, it was necessary to determine the free fraction in each plasma sample. Thirdly, due to the short half-life of prednisolone no steady-state is achieved, and therefore area under the concentration-time curve needed to be determined in all studies. Fourthly, prednisolone and prednisone are interconvertible and prednisolone is given intravenously as an ester prodrug, features which created controversies about the correct interpretation of pharmacokinetic results. Finally, the total body clearances of total and (to a lesser degree) of unbound prednisolone increase with increasing concentrations of prednisolone. Therefore, in order to compare pharmacokinetic results between different subjects, standardised doses had to be administered. The investigations performed so far have revealed that: (1) the dose-dependent pharmacokinetics partly explain the clinical observation that an alternate-day regimen with prednisone yields fewer biological effects; (2) the interconversion of prednisone into prednisolone is not a limiting factor, even in patients with severely impaired liver function; (3) hypoproteinaemia per se does not cause increased unbound concentrations of prednisolone in vivo; (4) patients with liver failure, renal failure or a renal transplant, subjects older than 65 years, women on estrogen-containing oral contraceptive steroids or subjects taking ketoconazole have increased unbound concentrations of prednisolone-whereas hyperthyroid patients, some patients with Crohn's disease, subjects taking microsomal liver enzyme-inducing agents or patients on intravenous prednisolone phthalate (instead of prednisolone phosphate) or on some brands of enteric coated prednisolone tablets have decreased concentrations of prednisolone. The biological relevance of the altered pharmacokinetics is supported in part by altered clinical effects and altered effects on cellular immunofunctions.
Animals↗
Impaired liver function in stable renal allograft recipients.
Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.
Cyclosporins↗
Study of acute renal ischemia in the rat using magnetic resonance imaging and spectroscopy.
Magnetic resonance (MR) imaging and spectroscopy, chemical lactate measurements, and microscopic examinations were performed to investigate acute renal ischemia in rats. MR images (1H) and spectra (31P and 1H) were acquired on a 2.0-T superconducting small-bore magnet by using implanted coils. Occlusion of the renal artery induced a significant decrease in signal intensity of the renal parenchyma on T2-weighted images, which was most obvious in the outer medulla (-50 +/- 15%, n = 8, P less than 0.001) and was the result of venous congestion, as verified histologically, 31P spectroscopy demonstrated a drop in pH from 7.3 +/- 0.2 to 6.6 +/- 0.2 (n = 18, P less than 0.001), characterized by a time constant (Tc) in the same range as that of the depletion of ATP (2.3 +/- 1.3 min versus 1.9 +/- 1.2 min, n = 10, P = ns). By means of 1H spectroscopy, a lactate peak was detected within 1.5 to 4 min of ischemia, still increasing in intensity after 1 h of ischemia. The Tc of the lactate buildup (15.9 +/- 7.5 min, n = 8) was significantly longer than that of the drop in pH (P less than 0.005). The chemically measured intrarenal concentration of lactate was 1.3 +/- 0.5 mumol/g in control kidneys and 8.7 +/- 3.2 mumol/g (P less than 0.005) in kidneys made ischemic for 1 h. The present study demonstrated important features of acute renal ischemia: (a) acute ischemia induces venous congestion in the medulla; (b) accumulation of lactate is not the main cause of the intracellular acidification observed during ischemia.
Animals↗
High haemodialysis clearance of ornidazole in the presence of a negligible renal clearance.
The pharmacokinetics of ornidazole was studied in 6 patients treated by haemodialysis and in 8 subjects with a creatinine clearance between 4 and 99 ml/min x 1.73 m2. Blood and urine collections were performed for 72 h after i.v. and oral administration of 1.0 g ornidazole. Total body clearance, half-life, volume of distribution and systemic availability were independent of renal function and did not differ from previously reported values in normal volunteers. The haemodialysis clearance of ornidazole was greater than 100% higher than the total body clearance. The renal clearance of ornidazole accounted for less than 7% of the total body clearance. The percentage of the dose of ornidazole recovered in urine as parent compound or as the biologically active metabolites [alpha-(chloromethyl)-2 hydroxymethyl-5 nitroimidazole-1 ethanol and 3-(2 methyl-5 nitroimidazole-1-yl)1,2 propanediol] decreased linearly with decreasing renal function. Although the sum of those three compounds recovered in urine accounted for less than 10% of the total dose of ornidazole administered, they yielded therapeutic concentrations (greater than 4 micrograms/ml) in urine over 24 h after dosing. Due to the peculiar pharmacokinetic behaviour of ornidazole, i.e. high haemodialysis clearance in the absence of significant renal clearance, no dosage adjustment is necessary while renal function declines, but an increased dose is mandatory while patients are on dialysis.
Administration, Oral↗
Impact of ketoconazole on the metabolism of prednisolone.
The impact of ketoconazole (200 mg for 7 days) on the kinetics of oral prednisone and intravenous prednisolone and on the apparent activity of the 6 beta-hydroxylase was investigated in 10 healthy volunteers. The ratio of urinary 6 beta-OH-cortisol/17-OH-corticosteroids declined by greater than 50% and the urinary excretion of 6 beta-OH-prednisolone decreased more than twofold in all subjects. The decline of the activity of the 6 beta-hydroxylase was associated with impaired metabolic and renal clearances of total and unbound prednisolone. The ratios of the AUCs of prednisolone/prednisone after oral prednisone and intravenous prednisolone were independent of the administration of ketoconazole, suggesting that the enzymes responsible for the interconversion of prednisolone in equilibrium prednisone were not affected by ketoconazole. Thus ketoconazole inhibits 6 beta-hydroxylase and increases the exposure of the body to the biologically active unbound prednisolone after oral prednisone or intravenous prednisolone.
Adult↗
Cyclosporine kinetics in renal transplant patients as assessed by high-performance liquid chromatography and radioimmunoassay using monoclonal and polyclonal antibodies.
The area under the blood concentration vs. time curves of cyclosporine (24 hr) were determined nonspecifically by the polyclonal RIA, specifically by a monoclonal RIA and by HPLC after an oral and an i.v. dose of CsA in 10 renal transplant patients. The mean blood concentrations determined by monoclonal RIA were 10-20% higher than those measured by HPLC, whereas the concentrations assessed by polyclonal RIA were greater than 100% higher than those determined by HPLC. As a corollary, the pharmacokinetic parameters (clearance, volume of distribution, and systemic availability) differed when the results from the 3 methods were compared. The RIA/HPLC concentration ratio of CsA was higher after oral than after i.v. dosing when RIA measurements were performed by the polyclonal but not by the monoclonal RIA. These ratios changed continuously during the first 12 hr after the administration when the polyclonal but not when the monoclonal RIA was used. In conclusion, blood concentrations assessed by the 3 methods are not identical, and when compared with the polyclonal RIA the monoclonal RIA exhibits 3 advantages: (1) much less crossreactivity with metabolites; (2) a constant RIA/HPLC concentration ratio after the third hr after administration of CsA; and (3) a RIA/HPLC concentration ratio that is independent of the route of administration.
Adult↗
Pharmacokinetics of acitretin and its 13-cis metabolite in patients on haemodialysis.
1. Plasma concentrations of acitretin and its metabolite (13-cis acitretin) were measured in six patients on haemodialysis and six subjects without renal failure following a single oral dose of 50 mg of acitretin. 2. The mean areas under the plasma concentration vs time curves of acitretin and its metabolite were about 50% lower in patients on haemodialysis. 3. No retinoids were detectable in the dialysate.
Acitretin↗
Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency.
The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.
Administration, Oral↗
Pharmacokinetics and metabolism of intravenous and oral fleroxacin in subjects with normal and impaired renal function and in patients on continuous ambulatory peritoneal dialysis.
The pharmacokinetics of fleroxacin, including the formation of N-demethyl and N-oxide fleroxacin after the administration of single intravenous (100-mg) and oral (400-mg) doses, was investigated in 26 subjects with various levels of renal function, including 7 patients on continuous ambulatory peritoneal dialysis. Fleroxacin was well tolerated by all subjects. The volume of distribution, systemic availability, and peak concentration after the administration of oral fleroxacin were independent of the glomerular filtration rate. As a consequence of a declining renal clearance but not nonrenal clearance, the total body clearance of fleroxacin declined with decreasing glomerular filtration rate from 1.41 +/- 0.23 ml/min per kg in subjects with normal renal function to 0.58 +/- 0.13 ml/min per kg in patients with end-stage renal disease (r = 0.84, P less than 0.001). The analysis revealed that the N-oxide metabolite exhibited formation-limited kinetics and the N-demethyl metabolite exhibited elimination-limited kinetics. The areas under the curve of both metabolites increased with declining renal function. In patients on continuous ambulatory peritoneal dialysis the mean dialysate/plasma concentration ratio of fleroxacin increased from 0.52 +/- 0.11 to 0.71 +/- 0.13 (P less than 0.001) with increasing dwell time, resulting in a 7.8 +/- 3.6% recovery of unchanged fleroxacin in peritoneal dialysate. In conclusion, (i) a 50% reduction of the maintenance dose is recommended in patients with a renal function below 20 to 30 ml/min per 1.73 m2, and (ii) therapeutic concentrations of fleroxacin in the peritoneal dialysate should be achievable after oral administration in patients on continuous ambulatory peritoneal dialysis.
Administration, Oral↗
Effect of thyroid dysfunction on thigh muscle efficiency.
To establish whether muscle weakness in thyroid dysfunction can be attributed solely to muscle atrophy (i.e. reduction in the total muscle cross-section) or whether the intrinsic contractile strength of the muscle is reduced per unit cross-sectional area, the ratio between thigh muscle strength and thigh muscle area was determined before and after treatment of hyper- and hypothyroidism. Midthigh muscle areas, assessed by computer tomography, increased in all seven hyperthyroid and decreased in three of four hypothyroid patients investigated after treatment of the thyroid disease. Peak torque and total work output, assessed by an isokinetic dynamometer (Cybex II), increased in both groups of patients. The muscle efficiency (total work output per cm2 muscle) increased in all patients after therapy [mean +/- SD values before vs. after therapy in hyperthyroid patients, 17.6 +/- 5.3 vs. 30.5 +/- 3.7 joules (J)/cm2 (P less than 0.001); in hypothyroid patients, 12.8 +/- 6.1 J/cm2 vs. 25.8 +/- 8.6 J/cm2 (P less than 0.05)]. Thus, the present study demonstrates that patients with thyroid dysfunction have altered muscle mass and diminished muscle efficiency.
Adult↗
Trough levels and concentration time curves of cyclosporine in patients undergoing renal transplantation.
We determined the AUC of cyclosporine (24 hours) nonspecifically by RIA and specifically by HPLC after an oral and an intravenous dose of cyclosporine in 58 patients undergoing renal transplantation. The RIA/HPLC concentration ratio of cyclosporine changed continuously during the first 12 hours after administration. The ratio was higher after oral than after intravenous administration and varied from patient to patient. The predictive value of trough levels for the corresponding AUCs was better when trough levels were assessed 24 than 12 hours after administration. Trough levels assessed by RIA poorly predicted AUCs measured specifically by HPLC. Therefore if, in the future, therapeutic cyclosporine monitoring has to be improved, trough levels should be assessed 24 hours after the last dose by means of a specific HPLC method.
Adult↗
Altered metabolism and decreased efficacy of prednisolone and prednisone in patients with hyperthyroidism.
To evaluate the effect of hyperthyroidism on the protein binding and metabolism of prednisolone, eight subjects with hyperthyroidism were investigated before and after thyroid status returned to normal. Hyperthyroidism was associated with a reduced volume of distribution of prednisolone, a decreased systemic availability of prednisolone after oral prednisone, a displacement of the prednisolone in equilibrium with prednisone equilibrium toward prednisone, and an increased nonrenal clearance of unbound prednisolone in the presence of an impaired 6 beta-hydroxyprednisolone formation. After oral prednisone or intravenous prednisolone, patients with hyperthyroidism had lower albumin-bound, transcortin-bound, and unbound concentrations of prednisolone but normal affinities of albumin and transcortin for prednisolone binding. These differences in prednisolone plasma concentrations were biologically relevant, because the capacity of these plasma samples to inhibit allogeneically stimulated lymphocytes was lower by 70% in the hyperthyroid than in the euthyroid state. Thus hyperthyroidism reduces the biologic effect of prednisolone and exhibits a differential effect on various enzymes involved in the catabolism of prednisolone.
Administration, Oral↗
Kinetics of prednisolone and endogenous cortisol suppression in the elderly.
The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.
Administration, Oral↗
[Radiologic diagnosis of early complications following kidney transplantation].
Postoperative complications after renal transplantation, such as hematomas, abscesses, urinomas, lymphoceles and obstruction of the ureter, can be diagnosed by means of sonography. Early vascular complications, such as venous thrombosis and arterial occlusion or stenosis, can be recognized by duplex sonography and accurately depicted by angiography to allow planning of surgical intervention. Stenosis of the renal artery is amenable to treatment by percutaneous angioplasty. Parenchymatous complications (acute tubular necrosis, acute rejection, cyclosporin-A-toxicity) can cause changes in the intrarenal flow patterns at duplex sonography, but this examination does not allow accurate diagnosis and differentiation of these changes. Magnetic resonance imaging is a very promising method for the differential diagnosis of parenchymatous complications.
Humans↗