Endogenous and exogenous glucocorticoids in cushingoid patients

The pharmacokinetics of prednisone/prednisolone and the time-course of endogenous hydrocortisone were investigated in 15 stable renal transplant patients and 12 patients with oral mucocutaneous vesiculoerosive diseases. All 27 patients were given their usual prednisone dose orally on one occasion, and 24 were given an equivalent amount of prednisolone intravenously on another occasion. After dosing, 8-14 plasma samples were obtained for the determination of total prednisolone, prednisone, and hydrocortisone concentrations by high performance liquid chromatography and unbound prednisolone concentrations by equilibrium dialysis. The bioavailability of prednisone, the interconversion of prednisone into prednisolone, the total and unbound prednisolone clearances, the prednisolone binding capacity of albumin and transcortin, and the affinity of albumin for prednisolone were not different when the 14 patients without cushingoid side effects were compared with the 13 cushingoid patients. Patients with cushingoid side effects had a higher affinity constant for prednisolone binding to transcortin, more frequently exhibited peak hydrocortisone levels within the normal range, and more often had measurable (greater than 10 ng/ml) hydrocortisone in the plasma samples collected during the kinetic studies, as compared with those not showing side effects. The data suggest that endogenous hydrocortisone production is not as suppressed in patients with visible cushingoid signs as in noncushingoid patients and that no significant difference in the pharmacokinetics of exogenous glucocorticoids exists between patients with and without cushingoid side effects.     

Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone

Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p<0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p<0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p<0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.     

The effect of prednisone and hydrocortisone on the plasma protein binding of prednisolone in man

Summary The protein binding of prednisolone was studied in plasma obtained from healthy volunteers in the presence of added amounts of prednisone and hydrocortisone. The plasma protein binding was determined using in vitro equilibrium dialysis for 16 h at 37°C against isotonic Krebs-Ringer buffer using radioactive prednisolone. Prednisone appeared to have no effect on prednisolone binding. This surprising result was observed even when prednisone concentrations were more than 35 fold greater than prednisolone concentrations. In contrast, a marked competition between hydrocortisone and prednisolone was observed. These binding data were fit using a nonlinear least squares regression computer program and the capacity and affinity constants for the binding of prednisolone to transcortin and albumin were estimated including the competition for binding sites between prednisolone and hydrocortisone. The results from these studies compare favorably with recent parameter calculations, and our previous work where differences in binding were noted between cushingoid and noncushingoid patients.     

The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users

The macromolecular binding of prednisone has been studied in the plasma of eight healthy human volunteers. The subjects included two control males, two control females, two females taking estrogen-containing oral contraceptives, and two females in the third trimester of pregnancy. All volunteers exhibited the expected nonlinear plasma binding of prednisolone with free fraction increasing as the total prednisolone concentration was increased. Both the oral contraceptive and pregnant subjects had increased transcortin binding capacity over the control volunteers as evidenced by their increased binding of prednisolone. Prednisone macromolecular binding, however, was not altered by either changing total prednisone concentration or transcortin binding capacity. The mean prednisone free fraction was 0.250 ± 0.027 in the eight subjects over the concentration range 0–2500 ng/ml. The addition of prednisolone in up to a 25- fold excess did not alter prednisone's free fraction. Prednisone apparently does not bind to transcortin with the same strong affinity that characterizes prednisolone's binding, and due to albumin's extensive binding capacity, prednisone macromolecular binding is not saturable over the pharmacological drug concentration range.Supported in part by NIH grant GM 26691. During the course of this work Linda E. Gustavson received support as the American Foundation for Pharmaceutical Education Edwin L. Newcomb Memorial Fellow.     

Nonlinear plasma protein binding and haemodialysis clearance of prednisolone

Summary The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10–100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8±4.4 µg/min, ± SE), was predictable from the afferent-efferent blood concentration differences (20.1±4.8 µg/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1±3.0 µg/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r ²=0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r ²=0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.Abbreviations Used C_Ba Afferent blood concentration [ng/ml] - C_Be Efferent blood concentration [ng/ml] - C_D Dialysate concentration [ng/ml] - C_Pa Afferent plasma concentration [ng/ml] - C_PaFree Free concentration of prednisolone in afferent plasma [ng/ml] - C_Pe Efferent plasma concentration [ng/ml] - CAP_A Binding capacity of albumin [µg%] - CAP_T Binding capacity of transcortin [µg%] - Cl_B Blood clearance [ml/min] - Cl_Free Free plasma clearance [ml/min] - Cl_P Plasma clearance [ml/min] - H_a Haematocrit in afferent blood - H_e Haematocrit in efferent blood - K Partition coefficient between red blood cells and plasma - KD_A Dissociation constant of albumin (M/L) - KD_T Dissociation constant of transcortin (M/L) - Q_B Blood flow [ml/min] - Q_D Dialysate flow [ml/min] - Q_F Flow of ultrafiltrate [ml/min] - t₁ First sampling time point after haemodialysis started - t₂ Last sampling time point before haemodialysis was discontinued - Z_Ddi Loss of prednisolone in the dialysate by diffusion [µg/min] (Z indicates calculated for each sampling time point) - _Ddi Mean loss of prednisolone in the dialysate by diffusion [µg/min] ( indicates calculated for the entire haemodialysis period) - Z_Dtot Total amount of prednisolone recovered in the dialysate [µg/min] - _Dtot Mean total amount of prednisolone recovered in the dialysate [µg/min] - Z_Du Loss of prednisolone in the dialysate by ultrafiltration [µg/min] - _Du Mean loss of prednisolone in the dialysate by ultrafiltration [µg/min] - Z_cB Amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min] - _cB Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min] - Z_cP Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min] - _cP Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min] - Z_cPK Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected by the partition coefficient [µg/min] - _cPK Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected for the partition coefficient [µg/min] Abstract presented to the American Society of Nephrology, Washington, 1981     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Pharmacokinetics of fluocortolone in man

Summary The kinetics of the synthetic corticoid fluocortolone was determined in 9 healthy female volunteers after a single oral dose of 20 mg. The maximal plasma level fluocortolone (C_max) of 202±70 ng/ml occurred within 85±32 min of oral intake after which it declined monoexponentially. Total plasma clearance was 6.48±2.07 ml/min·kg and the clearance of unbound fluocortolone was 60.38±26.67 ml/min·kg. Plasma protein binding was 83 to 95%. The volume of distribution at steady-state was 1.01±0.34 l/kg for total fluocortolone and 11.21±3.77 l/kg for unbound drug. The results of the study characterize the kinetics of unbound fluocortolone for the first time. In addition, the kinetics of total fluocortolone presented here confirm values calculated previously.     

Plasma protein binding of prednisolone in normal volunteers and arthritic patients

Summary The plasma binding of prednisolone was studied in twenty normal volunteers and twenty rheumatoid arthritis patients. An in vitro assessment of the binding following the addition of prednisolone, prednisone, and hydrocortisone to the plasmas obtained from the subjects showed significant differences in the percentage of prednisolone bound. However, the differences observed were regarded as clinically insignificant. The plasma protein binding was determined by an in vitro equilibrium dialysis of the individual plasma samples at 37° C. Prednisolone levels on both sides of the dialysis membrane were determined using radioactivity and HPLC analytical methodologies. The percentages of prednisolone bound calculated from the analytical results of either the radiochemical or HPLC method were not significantly different. The change in the percentage of prednisolone bound to plasma proteins was studied as a function of the total prednisolone plasma concentration in a normal volunteer and in a systemic lupus erythematosis patient. As a result of prednisolone binding to both transcortin and albumin, the binding of prednisolone changes as a function of prednisolone concentration. The binding data were fitted using nonlinear least squares regression, and the affinity constants for the binding of prednisolone to transcortin and albumin were estimated.     

Monitoring prednisone and prednisolone

Their common clinical use, frequency of adverse effects, serious therapeutic indications, treatment failures, and availability of sensitive assays make corticosteroids such as prednisone and prednisolone candidates for therapeutic drug monitoring. Complicating the interpretation of plasma drug concentrations are the first-pass metabolism of inactive prednisone to active prednisolone and reconversion. Also, the volume of distribution, metabolic clearance, and renal clearance of prednisolone increase with dose. This is due partly to saturable binding of prednisolone to transcortin in plasma, which provides more unbound drug at higher plasma concentrations of steroid. This effect plus the probable uptake of only unbound drug into intracellular receptor sites provides the rationale for measuring free prednisolone in plasma. Drug interactions between prednisolone and anticonvulsants are common. Liver and kidney disease have only limited effects on prednisolone disposition. Changes in clinical efficacy and appearance of side effects have been related to altered prednisolone clearance. Plasma concentrations may be used to determine disease and drug interactions, bioavailability, and patient compliance. The role of pharmacokinetic factors in governing the indirect and variable pharmacodynamic response to corticosteroids at various tissue sites and in disease states currently needs clarification.     

Pharmacokinetics of prednisone and prednisolone at steady state in the rabbit

A range (approximately 0.2-2.0 micrograms/min/kg) of constant rate iv infusions of prednisolone (as the phosphate ester) was administered to five rabbits either singly or as two consecutive infusions, and then again at about the same rates of infusion as part of multiple infusion studies. Prednisone (as the succinate) was also infused at three different infusion rates (range, 1.5-15 micrograms/min/kg) to four of the five rabbits. Plasma concentrations of prednisolone and prednisone at steady state were measured by HPLC. The binding of prednisone and prednisolone in plasma was measured by equilibrium dialysis. The multiple infusion studies demonstrated that the nonlinearity in plasma clearance of prednisolone could not be attributed to any time-dependent effect. The average plasma clearance of prednisolone increased by 250% when its rate of infusion was increased 10-fold. The ranges of clearance values at low and high rates of infusion were 2.51-4.08 and 6.08-10.98 ml/min/kg, respectively. The binding of prednisolone in plasma was found to be concentration dependent. At the lower rates of infusions, the clearance of unbound prednisolone appeared to increase on increasing its rate of infusion but remained relatively constant thereafter (greater than 1.0 microgram/min/kg). The ranges of unbound plasma prednisolone clearance at low and high rates of infusions were 30.3-67.7 and 50.6-110.2 ml/min/kg, respectively. The percentage of unbound prednisone increased on increasing the total plasma prednisone concentration (ranges at low and high concentrations of prednisone were 15.5-33.7 and 32.3-47.6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal action of adenosine: Effect on renin secretion in the rat

Summary The present study was undertaken to further evaluate the interaction of adenosine and the renin angiotensin system. In 12 sodium-restricted (SR) Sprague-Dawley rats plasma renin activity in the arterial carotid (PRA_a) and the renal venous (PRA_v) blood was measured using a radioimmunoassay for angiotensin I (AI). Renin secretion rate (RS) was calculated from the arteriovenous difference of PRA and renal plasma flow obtained from the reading of an electromagnetic flowmeter and hematocrit. Adenosine infused into the thoracic aorta at a rate of 33 nmol/min·100g body weight, decreased RS from 250±29 ng AI/min in the control periods to 115±17 ng AI/min (P<0.001, n=9). After cessation of the adenosine infusion RS recovered incompletely to 167±21 ng/AI/min. Adenosine reduced glomerular filtration rate (GFR) by 56% (P<0.001) but renal blood flow (RBF) by only 20%. The effects of adenosine were also studied in a group of sodium loaded (SL) rats. In 6 non-laparotomized SL rats (PRA_a=16±5 ng AI/ml·h) GFR was not significantly changed following adenosine infusion (1.54±0.16 vs 1.42±0.09 ml/min). In additional 7 SL rats (PRA_a=39±4 ng AI/ml·h) in which RBF was measured with an electromagnetic flow probe, adenosine reduced GFR by 20% (P<0.01), whereas RBF increased from 13.7±1.2 to 16.5±2.2 ml/min (P<0.05). RS in SL rats was not affected by adenosine infusion (59±16 vs 62±26 ng AI/min). There was a close correlation between the adenosine induced decrease of GFR and PRA_a (r=0.91, n=25) suggesting a higher sensitivity of the renal vasculature to adenosine when the renin-angiotensin system was stimulated. Micropuncture experiments in 9 Sprague-Dawley rats on a normal sodium diet demonstrated that adenosine infused in the low dose of 5 nmol/min·100 g of body weight markedly decreased the superficial nephron GFR from 38.6±2.65 to 20.5±1.67 nl/min (P<0.001) whereas whole kidney GFR was not changed significantly. This disproportionate response of superficial nephron compared to whole kidney GFR indicates that adenosine affects preferentially the superficial nephrons. It is concluded that adenosine depresses the renin secretion in SR rats. This depression was accompanied by a marked fall of the GFR. The renal response to adenosine was nearly abolished in SL rats suggesting that the renal action of adenosine is functionally related to the reninangiotensin system.Supported by Deutsche Forschungsgemeinschaft (Os 42/2)     

The dose-dependent systemic availability of prednisone: one reason for the reduced biological effect of alternate-day prednisone.

An analysis of the literature was performed, revealing that in many studies both the desired and the undesired effects are decreased in alternate-day prednisone regimens as compared with the daily regimens. In the present report evidence is given that part of the diminished biological effect of dose-spacing regimens is attributable to a decreased total exposure to prednisolone. Following a high dose of 0.8 mg kg-1 of oral prednisone or prednisolone the plasma concentration vs time curves of total prednisolone, unbound prednisolone and prednisolone bound to albumin or transcortin were always less than four times higher than following a low dose of 0.2 mg kg-1 of prednisone or prednisolone. This dose-dependent systemic availability of prednisolone explains partly the diminished biological effect when the same total amount of prednisone or prednisolone is divided into several small doses as opposed to a single oral dose.     

A Pharmacokinetic Comparison of Two Oral Liquid Glucocorticoid Formulations

To compare pharmacokinetics of liquid prednisolone and prednisone solutions and to assess relative bioavailability, six healthy adult men were administered 15 mg of each formulation. Blood samples were obtained and assayed for plasma prednisolone concentrations by high-performance liquid chromatography. Peak concentration was significantly higher with liquid prednisolone (mean ± SD 430.3 ± 62.5 vs 333.0 ± 27.8 ng/ml, p=0.013), with similar times to peak concentration. Prednisolone liquid gave higher concentrations at every time point (statistically significant for all except 0.25 hrs after the dose), resulting in a significantly greater total area under the curve (2029.8 ± 246.9 vs 1633.3 ± 221.1 ng/ml•hour, respectively, p=0.002). Clearance was slower for prednisolone (128.3 ± 15.1 vs 149.1 ± 17.6 ml/min/1.73 m², p=0.01), and the relative bioavailability of the prednisolone liquid using prednisone liquid as the reference standard was 116 ± 14%. Thus, prednisolone liquid has similar pharmacokinetic characteristics as prednisone liquid, with improved bioavailability.     

Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis

Summary The pharmacokinetics of diflunisal, a salicylate derivative that undergoes phenolic and acyl glucuronidation as well as sulphate conjugation, has been studied after a single oral dose (250 mg) in patients with cirrhosis (n=5) and in healthy controls (n=5).The plasma clearance of total (bound + unbound) diflunisal was 10.2 ml · min^–1 in the control subjects and it was not affected by cirrhosis (10.9 ml · min^–1). The plasma protein binding of diflunisal was significantly reduced in cirrhosis; the percentage of unbound diflunisal in plasma was 0.089 in the controls and 0.147 in the patients with cirrhosis. Plasma clearance of unbound diflunisal was significantly impaired in cirrhosis: 11.51 · min^–1 in control subjects vs 7.41 · min^–1 in cirrhotics.In cirrhotic patients, the unbound partial clearances to the phenolic and acyl glucuronides were both significantly reduced, by approximately 38%. The unbound partial clearance to the sulphate conjugate was not significantly affected by cirrhosis.The results show that both the phenolic and acyl glucuronidation pathways of diflunisal are equally susceptible to the effects of liver cirrhosis.     

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.     

Effects of Acute and Chronic Inflammation on the Pharmacokinetics of Prednisolone in Rats

The effects of acute and chronic stages of carrageenan-induced air-pouch inflammation on the pharmacokinetics of prednisolone were studied in male Wistar rats. Chronic inflammation produced a significant increase in the area under the curve (AUC) of prednisolone compared to control animals (6594 ± 2144 vs 3530 ± 2164 µg · hr/ L). The effect of acute inflammation was not significant (AUC = 4996 ± 3813). Both acute and chronic inflammation also reduced thein vitro plasma protein binding of prednisolone, the reduction being much greater after chronic inflammation. The AUC of free prednisolone after chronic inflammation was 3141 µg · hr/L, compared to 1121 µg · hr/L in the control group and 1823 µg · hr/L after acute inflammation. The mean values of half-life and apparent volume of distribution at steady-state in each group were similar. These results indicate that prednisolone must be used with caution in the treatment of inflammatory diseases because of higher free concentrations of the steroid.     

Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing

Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid Chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80–100 mg/liter. The clearance of sulfisoxazole was 18.7±3.9ml/min for total drug and 232±64ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9±2.0 liters and 136±36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95±0.04.Supported in part by grant GM 25807 from the National Institutes of Health.     

Comparison of acute and subacute effects of deflazacort and prednisone on glucose metabolism in man

Summary Corticosteroid treatment produces glucose intolerance with insulin resistance. Recent reports have indicated that deflazacort (DF) is significantly less diabetogenic than prednisone (PN). A euglycaemic hyperinsulinaemic (100 µU/ml) glucose clamp (EHGC) and ³H-glucose infusion for 240 min were performed in 6 healthy volunteers (HV) after administration of 15 mg PN or 18 mg DF, 12 h and 2 h before test. The glucose metabolic clearance rate (MCR) was significantly (p=0.02) higher after DF (4.75±0.58 ml/min·kg) than after PN (3.31±0.27 ml/min·kg). Basal hepatic glucose production (HGP) was significantly (p=0.003) lower after DF (3.58±0.33 mg/kg·min) than after PN (4.44±0.23 mg/kg·min). A similar pattern was obtained for glucose volume (GV) and glucose pool (GP). The kinetic parameters of insulin were not significantly different after the two drugs. After 7 day of PN 30 mg/day or DF 36 mg/day, EHGC and ³H-glucose infusion for 240 min were performed in 10 HV. Glucose MCR values were significantly (p=0.03) higher after DF (5.03±0.91 ml/min·kg) than after PN (2.80±0.26 ml/min·kg). HGP values did not different significantly after the two drugs. GV (p=0.001) and GP (p=0.002) were significantly lower after DF than after PN. Insulin kinetics were not significantly different after the two drugs. It is concluded that on acute and 7-day administration to healthy subjects DF, in an anti-inflammatory dose equivalent to PN, shows significantly less influence on glucose metabolism.     

Comparative disposition of pethidine and norpethidine in old and young patients

Summary Pethidine was given as a single intravenous dose for premedication before minor surgery. Two groups of subjects were studied, old patients aged more than 65 years, and young patients aged 18–30 years. Blood samples were taken at fixed intervals for 30 h after the injection, and the plasma concentrations of pethidine and its major metabolite norpethidine were analyzed by gas chromatography. In comparison with the young the old patients had a lower plasma clearance for pethidine (9.13±2.50 versus 16.18±5.15 ml/min/kg), slower elimination rate (0.101±0.036 versus 0.211±0.146), and a larger AUC (1935±554 versus 1092±277 h · ng/ml) but a similar volume of distribution (5.69±1.54 versus 5.38±1.75 l/kg). Norpethidine appeared later and reached its peak concentration later in the old patients than in the young. In several old patients it was still present at a plateau level after 30 h. The present study emphasizes that both parent drug and active metabolite must be taken into consideration when drug therapy is evaluated. The data do not provide pharmacokinetic support for a reduction in the dose of pethidine if it is given as a single intravenous dose. However, when repeatedly administered, it is advisable to reduce the total daily dose.This study was presented in part at the World Conference on Clinical Pharmacology and Therapeutics, London, 3–9th August 1980     

Plasma glucose lowering effect of spartein sulphate infusion in non-insulin dependent (Type 2) diabetic subjects

Summary Sparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2±2.8 to 26.4±4.2 mg · kg^–1 · min^–1 (p<0.01), and it was potentiated by simultaneous infusion of arginine.No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1±0.8 vs 2.6±1.2 mg · kg^–1 · min^–1) was not statistically significant different in the last 60 min of the experiment.It is concluded that sparteine sulphate enhances -cell secretion, causing a fall in the plasma glucose concentration.