Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration

The pharmacokinetic profile of (+/-)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (+/-)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr-1. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg.hr/liter, respectively. The bioavailability of a single oral dose of (+/-)-gossypol in rats was 60%. The change in plasma (+/-)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (+/-)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (+/-)-gossypol was eliminated at a rate constant of 0.01 hr-1, corresponding to half-life of 64.76 hr. Subchronic oral administration of (+/-)-gossypol showed an apparent half-life of 101.91 hr-1, corresponding to a rate constant of 0.007 hr-1. The results indicate that multiple oral dosing of (+/-)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (+/-)-gossypol may play, at least in part, a role in the reproductive toxicity of subchronic but not single oral dosing.     

Dose-dependent inhibition of cyclosporine metabolism in mice by fluconazole

Fluconazole, a potent bis-triazole antimycotic drug, has been demonstrated to inhibit antipyrine metabolism, a cytochrome P-450 dependent process, in vivo in mice. Cyclosporine is metabolized by the cytochrome P-450 enzyme system in both mice and man. We investigated whether fluconazole had any effects on the metabolism of cyclosporine in vivo in mice. The effects of three different doses of fluconazole (1, 5, and 20 mg/kg) on the metabolism of cyclosporine in CD-1 mice were studied in single-dose experiments. Fluconazole produced significant dose-dependent decreases in the elimination rate constant and increases in the terminal half-life of cyclosporine. The 1 mg/kg dose caused a 26% prolongation of the terminal half-life and the 5 and 20 mg/kg dose prolonged the half-life by 72 and 187%, respectively. Fluconazole doses in the 1-5 mg/kg range are effective in mouse models of fungal infections. These results provide further in vivo evidence that fluconazole is a potent inhibitor of the cytochrome P-450 dependent enzyme system in mice. Future experimental studies in animals and humans are needed to evaluate possible metabolic drug-drug interactions involving fluconazole.     

The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat

A method was developed for assessing non-steroidal anti-inflammatory compounds for their potency in blocking parturition, and prolonging gestation, in the rat. This consisted of injecting compounds into groups of 10 to 13 rat dams twice daily from Day 18 through Day 22 of pregnancy, and comparing the treated dams with appropriate controls on Day 23. The rate of blocked parturition appeared to be positively related to dose of non-steroidal anti-inflammatory agent and, therefore, this model and end-point appeared to be useful for assessing different non-steroidal anti-inflammatory compounds for potency. Among the twenty-seven non-steroidal anti-inflammatory agents evaluated by this method were: ibuprofen, phenylbutazone, tolmetin, flufenamic acid, 2(p-biphenyl) acetic acid, mefenamic acid, aspirin, fenoprofen calcium, flumazole, ketoprofen, naproxen, isoxicam, indomethacin, 2(p-biphenyl) propionic acid, 2(2′-fluoro-4-biphenyl) propionic acid, flurbiprofen, sudoxicam and piroxicam. Piroxicam, sudoxicam, flurbiprofen, 2(p-biphenyl) propionic acid and 2(2′-fluoro-4-biphenyl) propionic acid showed the greatest potency. The relationship between structure and activity and between the blocking of parturition and the inhibition of prostaglandin synthesis are discussed.     

Etodolac: effect on prostaglandin concentrations in gastric mucosa of rats

Etodolac is a structurally novel compound exhibiting potent analgesic and anti-inflammatory activity in laboratory animals and man, with excellent G. I. tolerance. Like other nonsteroidal anti-inflammatory drugs (NSAIDs) etodolac inhibits prostaglandin (PG) biosynthesis. In view of the cytoprotective role of PGE2, we have investigated in normal rats the effect of etodolac on the gastric mucosal concentration of PGE2 as well as of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin; naproxen and piroxicam served as reference NSAIDs. The orally effective anti-inflammatory doses in the chronic arthritic rat model (3 mg/kg for etodolac and naproxen; 0.5 mg/kg for piroxicam), and their arbitrarily selected multiples of 10 were used. Rats were killed at 1, 2, 6 and 24 hr after single doses and the PG concentrations were measured by RIA. With the low dose, 2 and 6 hr after dosing, etodolac diminished the PGE2 concentration by 20-25% (vs control) while naproxen and piroxicam caused a fall of 53-65%; the difference between etodolac and the untreated control group is not statistically significant but the difference between etodolac and both piroxicam and naproxen is significant (p less than 0.001). At the high doses, the lowering in PGE2 was similar after all three drugs, i.e. about 70% at 1 and 2 hr; 50% at 6 hr, and 20-50% at 24 hr after dosing. Except for the consistently smaller reduction of concentrations after etodolac, the effects on 6-keto-PGF1 alpha concentration followed a similar pattern but the differences are not significant. The lack of the G.I. irritation of etodolac in rats and man at therapeutically effective doses may be attributed to the benefits of the relatively short-lived and slight decrease in gastric mucosal PGE2 concentrations found in this study.     

Study of feline oral squamous cell carcinoma: potential target for cyclooxygenase inhibitor treatment

Oral squamous cell carcinoma (OSCC) is associated with high morbidity and mortality. A potential target for OSCC treatment is cyclooxygenase-2 (cox-2). Pet cats with naturally occurring OSCC may offer the opportunity to study anticancer activity of cox inhibitors. Cox-2 expression in feline OSCC was determined by immunohistochemistry. High intensity cox-2 immunoreactivity was detected in 6 of 34 (18%) feline OSCC samples. Weak immunoreactivity was noted in 22 OSCCs and in epithelial cells from oral mucosa of clinically normal cats. Pharmacokinetics of a cox inhibitor (piroxicam, 0.3 mg/kg) were studied in carcinoma-bearing cats to confirm a dose for follow-up trials. The average peak serum piroxicam concentration (948 ng/ml, which inhibited cox-2 activity) and serum half-life (15.9 h) were similar to that in normal cats. These results provide information (cox-2 expression as an inclusion criteria, 0.3 mg/kg daily piroxicam) for the design of follow-up trials of cox inhibitor treatment in pet cats with OSCC.     

Linear and Non Linear Competition Plots in the Deoxyribose Assay for Determination of Rate Constants for Reaction of non Steroidal Antiinflammatory Drugs with Hydroxyl Radicals

Performing the deoxyribose (DR) assay for determination of the rate constants for reaction of non steroidal antiinflammatory drugs with hydroxyl radicals led to some unusual competition plots. The molecules from the arylpropionic family of drugs: ibuprofen, flurbiprofen, ketoprofen and naproxen produced the linear relationship. However, acemetacin, diclofenac Na, flufenamic acid, indometacin, niflumic acid, tolmetin Na and sulindac presented non linear competition plots manifesting at relatively low drug concentrations. This effect was corrected by increasing DR concentrations from 2.8 mM to 15 mM. The modification did not affect rate constants values for those derivatives which already presented a linear plot at 2.8 mM, but allowed to calculate rate constants for other compounds. It is suggested that the experimental conditions have to be adapted particularly for those derivatives with a relatively high. rate constant for reaction with the radical species. The oxicam derivatives (tenoxicam and piroxicam) presented another kind of deviation that revealed a prooxidant effect in this system: non linear plots were also observed at relatively low drug concentrations, but in the opposite direction than for the other molecules. This last effect was independent of DR concentration but could be corrected by increasing ascorbate concentration in the system.     

Increased thyroxine turnover after 3,3',4,4',5,5'-hexabromobiphenyl injection and lack of effect on peripheral triiodothyronine production

Juvenile male Wistar rats were injected i.p. with 0, 20, or 40 mg/kg 3,3',4,4',5,5'-hexabromobiphenyl and blood samples collected periodically up to 28 days. A dose-dependent depression of the serum thyroxine level was detected, while the circulating triiodothyronine concentration was not affected by the biphenyl congener. Thyroxine turnover in vivo 7 days after injection of the 20 mg/kg dose revealed significant increases of various clearance parameters relative to controls. The fractional clearance rate (day-1) increased by 84%, the daily metabolic clearance rate (mL.kg-1.day-1) increased by 128%, and the daily thyroxine disposal rate (ng.kg-1.day-1) increased by 41%. Also, the thyroxine distribution space (mL/kg) increased by 21%. These results indicated greater thyroxine binding in major organs as well as a marked increase in the peripheral metabolism of thyroxine. The increased thyroxine metabolism is explained by a 4.8-fold induction of uridine 5'-diphosphoglucuronyltransferase activity in liver microsomes. The type I 5'-deiodinase activity in liver homogenates and endogenous concentrations of the cofactor for this reaction, glutathione, were not affected by the biphenyl. This result means that homeostatic mechanisms involving thyroxine conversion to triiodothyronine do not explain the maintenance of serum T3 under these conditions.     

Generalization of a prototype intelligent hybrid system for hard gelatin capsule formulation development

The aim of this project was to expand a previously developed prototype expert network for use in the analysis of multiple biopharmaceutics classification system (BCS) class II drugs. The model drugs used were carbamazepine, chlorpropamide, diazepam, ibuprofen, ketoprofen, naproxen, and piroxicam. Recommended formulations were manufactured and tested for dissolution performance. A comprehensive training data set for the model drugs was developed and used to retrain the artificial neural network. The training and the system were validated based on the comparison of predicted and observed performance of the recommended formulations. The initial test of the system resulted in high error values, indicating poor prediction capabilities for drugs other than piroxicam. A new data set, containing 182 batches, was used for retraining. The percent of the test batches were used for cross-validation, resulting in models with R²≥70%. The comparison of observed performance to the predicted performance found that the system predicted succcessfully. The hybrid network was generally able to predict the amount of drug dissolved within 5% for the model drugs. Through validation, the system was proven to be capable of designing formulations that met specific drug performance criteria. By including parameters to address wettability and the intrinsic dissolution characteristics of the drugs, the hybrid system was shown to be suitable for analysis of multiple BCS class II drugs. Published: October 22, 2005     

Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats

Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220–290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 μg/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg ix. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61)mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in heparic metabolism in response to chronic epoprostenol administration are nor expected.     

Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine.

OBJECTIVE: To evaluate the prophylactic effect of ranitidine 150 mg twice daily in patients requiring one of the following non-steroidal anti-inflammatory drugs: naproxen, piroxicam, diclofenac, and indomethacin. In addition, risk factors were studied in order to help in targeting of such treatment to specific groups of patients. DESIGN: Double blind, placebo controlled, randomised, parallel group with endoscopic assessments at 0, 4, and 8 weeks. SETTING: Multicentre outpatient study at secondary referral centres in five European countries. PATIENTS--297 patients with rheumatoid arthritis or osteoarthritis over the age of 18 without lesions in the stomach and duodenum at baseline endoscopy (after one week without taking non-steroidal anti-inflammatory drugs). Those taking other antirheumatic agents, concomitant ulcerogenic drugs, or treatment for peptic ulcers within the previous 30 days were excluded. Age, sex, arthritic disease, and type of non-steroidal anti-inflammatory drug used were comparable in the two treatment groups. In all, 263 patients completed the trial. INTERVENTIONS: Ranitidine 150 mg twice daily or placebo (plus the selected non-steroidal anti-inflammatory drug) was prescribed within five days after the baseline endoscopy for two consecutive periods of four weeks. Paracetamol was permitted during the study, but not antacids. Patients were withdrawn if the most severe grade of damage (including ulceration) was found at the four week endoscopy or when indicated, or with lesser damage at the investigator''s discretion. END POINT: Frequency of gastric and duodenal ulceration or lesions, or both. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of peptic ulceration by eight weeks was 10.3% (27/263); 2 out of 135 (1.5%) developed duodenal ulceration in the ranitidine group, compared with 10 out of 126 (8%) taking placebo. The frequency of gastric ulceration was the same (6%) for the two groups at eight weeks. Though significantly fewer gastric lesions developed in the ranitidine group by eight weeks. The frequency of non-ulcerative lesions in the duodenum did not differ greatly for the two groups at either time point. Twelve out of 75 (16%) patients taking piroxicam developed peptic ulceration, of whom two thirds had duodenal ulceration. Patients with a history of peptic ulcer were particularly susceptible to recurrent ulceration, against which ranitidine offered some protection. CONCLUSIONS: Ranitidine 150 mg twice daily significantly reduced the incidence of duodenal ulceration but not gastric ulceration when prescribed concomitantly with one of four commonly used non-steroidal anti-inflammatory drugs.     

Disappearance of [1alpha-3H]-chlormadinone acetate in the plasma and red cells of rhesus monkey.

The half-life and metabolic clearance rate of chlormadinone acetate in 4 rhesus monkeys was computed after iv injection. Chlormadinone was analyzed as total, free, and conjugated radioactivity, and as recrystallized chlormadinone acetate. 55.0 mc Ci, 222 mc Ci/mg was injected iv in 5 ml ethanolic saline. There was an initial rapid disappearance, half-life 68 minutes, and a slower disappearance, half-life 35.1 hours. These half-lives are much longer than those of estradiol and progesterone, but are shorter in monkeys than in women. The metabolic clearance rate of chlormadinone acetate was 102.6 liters/day. The half-life in red cells of 1 monkey was similar to those seen in plasma, but the amount of chlormadinone acetate was much less.     

Studies on the Absorption and Distribution of Doxycycline in Normal Patients and in Patients with Severely Impaired Renal Function

Doxycycline, a recently synthesized analogue of tetracycline, was given to 16 patients with normal renal function and to 14 patients with severely impaired renal function. Serum concentrations in the two groups following a single dose were followed after absorption. The rate of clearance from the plasma following a single dose did not differ significantly in the two groups despite low urinary concentrations in patients with renal failure. No accumulation of doxycycline occurred in the serum of three normal patients or of nine patients with renal failure when treated with either 200 mg. daily or 200 mg. initially followed by 100 mg. daily for up to 15 days.     

Salicylates inhibit paf-acether-induced rat paw oedema when cyclooxygenase inhibitors are ineffective

The cyclooxygenase inhibitors indomethacin, piroxicam, ibuprofen, naproxen and flurbiprofen failed to block rat paw oedema induced by PAF-acether, whereas aspirin and sodium salicylate were effective. Two mixed cyclooxygenase and lipoxygenase inhibitors NDGA, BW 755C and dexamethasone reduced oedema in a dose — dependently. The selective PAF-acether antagonist, BN 52021, was effective against PAF-acether at 5 – 20 mg/kg. The lipoxygenase derivates may be involved in paw oedema induced by PAF-acether in the rat and the inhibition produced by aspirin and by sodium salicylate should involve mechanisms other than the cyclooxygenase pathway.     

Changes in hepatic biotransformation in patients treated with beta-adrenergic drugs and prazosin

Biotransformation in the liver was tested with antipyrine elimination test in 41 patients treated with prazosin for 3 months (Minipress Pfizer, 1-4 mg a day) or prazosin combined with beta-adrenolytic agents (propranolol 40-80 mg; metoprolol 100-200 mg daily). It was found that T0.5 of antipyrine is shortened in patients treated with prazosin alone by 3 h/p greater than .05/while in the patients treated with prazosin whom previously--adrenalytics were given by 7.5 h/p greater than 0.01/. Antipyrine half-life during the treatment with beta-adrenolytics was prolonged by + 5.3 h/p greater than .05/while during the combined therapy with these agents and prazosin - 3.8 h. These results indicate that prazosin contrary to beta-adrenolytics, does not affect biotransformation in the liver. During combined therapy with prazosin and beta-adrenolytics, unfavourable effect of the latter in prevailing. Replacement of beta-adrenolytics with prazosin may prevent unfavourable effect of the former on liver functioning and may increase the safety of the hypotensive treatment.     

Plasma clearance and half-life of prostaglandin F2alpha: a comparison between mares and heifers

Horses are about five times more sensitive to the luteolytic effect of prostaglandin F2alpha (PGF) than cattle, as indicated by a recommended clinical dose of 5 mg in horses and 25 mg in cattle. Novel evaluations of the PGF plasma disappearance curves were made in mares and in heifers, and the two species were compared. Mares and heifers (n = 5) of similar body weight were injected (Min 0) intravenously with PGF (5 mg per animal). Blood was sampled every 10 sec until Min 3, every 30 sec until Min 5, every 10 min until Min 60, and every 30 min until Min 240. The mean PGF concentration was greater (P < 0.05) in mares than in heifers at Min 1 through Min 60 and at Mins 180 and 240. The mean time to maximum PGF concentration was not different between mares (42.0 ± 8.6 sec) and heifers (35.0 ± 2.9 sec). The apparent plasma clearance, distribution half-life, elimination half-life, and maximum plasma PGF concentration were 3.3 ± 0.5 L h(-1) kg(-1), 94.2 ± 15.9 sec, 25.9 ± 5.0 min, and 249.1 ± 36.8 ng/ml, respectively, in mares and 15.4 ± 2.3 L h(-1) kg(-1), 29.2 ± 3.9 sec, 9.0 ± 0.9 min, and 51.4 ± 22.6 ng/ml, respectively, in heifers. Plasma clearance was about five times less (P < 0.0005), maximum plasma PGF concentration was five times greater (P < 0.002), and the distribution half-life and elimination half-life were about three times longer (P < 0.005) in mares than in heifers. The fivefold greater plasma clearance of PGF in heifers than in mares corresponds to the recommended fivefold greater clinical dose of PGF in cattle and supported the hypothesis that the metabolic clearance of PGF is slower in mares than heifers.     

Simultaneous analysis of several non-steroidal anti-inflammatory drugs in human urine by high-performance liquid chromatography with normal solid-phase extraction

A practical and reproducible high-performance liquid chromatographic method using normal solid-phase extraction has been developed for the simultaneous analysis of twelve non-steroidal anti-inflammatory drugs (NSAIDs) in human urine. A urine specimen mixed with acetate buffer pH 5.0 was purified by solid-phase extraction on a Sep-Pak Silica cartridge. The analyte was chromatographed by a reversed-phase Inertsil ODS-2 column using a phosphate buffer-acetonitrile at pH 5.0 as the mobile phase, and the effluent from the column was monitored at 230 or 320 nm. Absolute recoveries were greater than 73% for all of the twelve NSAIDs. The present method enabled simple manipulation and isocratic HPLC with UV analysis as well as high sensivity of 0.005 μg/ml for naproxen, and 0.05 μg/ml for sulindac, piroxicam, loxoprofen, ketoprofen, felbinac, fenbufen, flurbiprofen, diclofenac, ibuprofen and mefanamic acid as the quantitation limit in human urine using indomethacin as an internal standard.     

Preclinical pharmacokinetics of MHAA4549A,a human monoclonal antibody to influenza A virus,and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A

MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ～2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.     

Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.

OBJECTIVE--To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGN--Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. SETTING--Hospital and community based case-control and cohort studies. MAIN OUTCOME MEASURES--(a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. RESULTS--12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS--The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.     

Kinetics of cortisol metabolism and excretion. A hypothetic model based on the cumulative urinary radioactivity in eight multiple pituitary deficient patients.

A new model is proposed to study the kinetics of [3H]cortisol metabolism by using urinary data only. The model consists of 5 pools, in which changes of the fractions of dose are given by a system of 5 ordinary differential equations. After i.v. administration of [3H]cortisol to 8 multiple pituitary deficient (MPD) patients (group I) the urines from each patient were collected in 9-15 portions during the following 3 days. From the urinary data the rate constants of cortisol metabolism were calculated. A published set of urinary data from patients with a normal cortisol metabolism (group II) was used for comparison. The overall half-life of the label in the circulation was 30 min for both groups; the half-life of the label excretion by both groups was 6 h and the time of maximal activity in the main metabolizing pool was 1.8 h in group I and 1.5 h in group II. The 20% of normal cortisol production rate (CPR) in the 8 MPD patients amounted to 7.2 +/- 1.9 mumol/(m2*d). Therefore, the low CPR but normal rate constants, i.e. a normal metabolic clearance rate of cortisol, in the MPD patients suggest a sensitive adjustment of the cortisol response in the target organs.