Comparison of the gastric antisecretory effects of ramixotidine dihydrochloride (CM 57755), a new H2 receptor antagonist, and cimetidine in dogs

This paper compares the effects of ramixotidine dihydrochloride (CM 57755) with those of cimetidine on gastric acid secretion and gastrin release in conscious dogs chronically fitted with Heidenhain pouches and/or gastric fistulae. At equimolar doses, intravenous (i.v.) or intragastric (i.g.) CM 57755 caused similar inhibition of dimaprit- or pentagastrin-induced secretion than cimetidine. Acid secretion stimulated by a meat meal was significantly reduced by both CM 57755 and cimetidine. Neither CM 57755 (4.5 and 9 mumol/kg) nor cimetidine (4 mumol/kg) modified gastrin release, while cimetidine (8 mumol/kg) significantly increased it. Judging from these results, while CM 57755 appears to be an inhibitor of gastric acid secretion induced by different stimulants in dogs with potency comparable to cimetidine. The increase in plasma gastrin levels seen after cimetidine but not after CM 57755 suggests that cimetidine releases gastrin by a mechanism independent of H2 receptor antagonism.     

Inhibition of dimaprit- and pentagastrin-induced gastric acid secretion in cats by the new histamine H2 antagonist, CM 57755

The antisecretory effects of CM 57755, a new histamine-H2 receptor antagonist, have been compared with those of cimetidine on gastric acid secretion induced by intravenous infusions of dimaprit or pentagastrin into conscious cats with chronically implanted gastric fistulae. Intravenous infusion of CM 57755 induced a parallel shift to the right of the dimaprit dose-response curve. The potency of CM 57755 was comparable with that of cimetidine as shown by similar doses causing a 5-fold displacement to the right of the dimaprit dose-response curve (4.9 mumol kg-1 h-1 for CM 57755 and 4.7 mumol kg-1 h-1 for cimetidine). Unlike that with dimaprit, the acid secretion stimulated by increasing doses of pentagastrin was inhibited by CM 57755 with depression of the maximal effect, indicating non-competitive antagonism. In a second series of experiments the time course of the anti-secretory action of intragastrically administered CM 57755 was studied from the gastric acid secretion induced by constant infusion of dimaprit. At equieffective doses, CM 57755 caused more sustained inhibition than cimetidine.     

Inhibition of pentagastrin-stimulated gastric acid secretion and plasma levels of the new histamine H2-receptor antagonist ramixotidine dihydrochloride (CM 57755) in human volunteers

Summary The new competitive histamine H₂-receptor antagonist, ramixotidine 2 HCl (CM 57755), has been tested in healthy male volunteers for its ability to inhibit pentagastrin-stimulated gastric acid secretion. In the first study, in 8 subjects, pentagastrin 6 µg·kg^–1 was injected s.c., 90 min after the following 4 oral treatments given in random order at weekly intervals: placebo, 100, 200 and 400 mg CM 57755. Gastric contents were collected over 15-min periods during the 2 h after pentagastrin stimulation. In a second, similar study, 8 subjects received placebo, 0.5 and 1.0 g CM 57755 and 800 mg cimetidine, 120 min before a 2 h i.v. infusion of 6 µg·kg^–1·h^–1 pentagastrin. Cumulative gastric secretion in placebo-treated subjects was 46±14 and 62±11 mmol H⁺·2 h^–1 (mean±SD), respectively, in the first and second studies. It was significantly reduced only after 400 mg CM 57755 in the first study. In the second study either dose of CM 57755 and cimetidine caused a significant reduction in gastric acid secretion. Average plasma levels of ramixotidine were dose-related after 0.2 and 1.0 g and ranged from 0.3 and 1.6 µg/ml, respectively, at 60 min to 0.5 and 3.7 µg/ml at 180 min. The peak cimetidine level averaged 3.6 µg/ml at 150 min. Individual CM 57755 plasma levels throughout the test period were fairly consistent with the inhibition of cumulative gastric acid secretion scored concurrently in each subject. No subjective side-effects attributable to the treatments were reported, and no abnormal findings were seen in the ECG or in laboratory tests.     

Gastric inhibitory effects of CM57755

Summary The gastric inhibitory effects of CM57755, a new histamine H₂ receptor antagonist, have been compared in ten healthy male volunteers with the actions of an equal dose of cimetidine and with placebo. The inhibitory effect of CM57755 was virtually identical with, and not significantly different from the effects of cimetidine on nocturnal gastric secretion of acid, while neither drug influenced the secretion of pepsin. Neither drug, administered in the evening, influenced the intragastric pH and acidity during the following day, from breakfast onwards. The therapeutic impact of the new drug is likely to resemble that of cimetidine and clinical application will depend on the safety profile.     

A Kinetic Model for Simultaneous Fit of Clozapine and Norclozapine Concentrations in Chronic Schizophrenic Patients during Long-Term Treatment

OBJECTIVE: The pharmacokinetic profiles of clozapine and its main metabolite, norclozapine, were investigated in 18 chronic schizophrenic inpatients during long-term treatment. PATIENTS: Patients received stable daily doses (between 300 and 900mg) for at least 1 month. Plasma drug concentrations were determined by high performance liquid chromatography. The pharmacokinetic parameters were calculated from both noncompartmental and compartmental approaches with zero-order input rate using a kinetic model for simultaneous fit of clozapine and norclozapine (active metabolite) concentrations. RESULTS: Large interpatient variations in pharmacokinetic parameters of the two drugs were observed. Plasma clozapine concentration peaked on average at 2 hours. The mean elimination rate constants from compartments 1 (k(10)) and 2 (k(20 ), elimination rate constant of norclozapine) were 0.087 and 0.156h(-1), respectively. The rate of formation of norclozapine, k(12), averaged 1.25h(-1). The mean fraction of the administered dose converted to norclozapine was estimated to be 66%. The apparent clearance of clozapine (CL/F) averaged 44.7 L/h and the volume of distribution (V(c)/F) was 7.00 L/kg. The pharmacokinetics of clozapine after multiple doses were linear over the range of clozapine plasma concentrations of 145 to 1411 microg/L. CONCLUSION: This is the first study assessing the pharmacokinetic profile of clozapine plus norclozapine in plasma during long-term treatment. This pharmacokinetic model can be used to determine the population pharmacokinetic parameters of clozapine and norclozapine in order to optimise individual dosage regimens using a Bayesian methodology.     

Pharmacokinetics of 2',3'-dideoxycytidine in rats: application to interspecies scale-up

The effects of dose on the pharmacokinetics of 2',3'-dideoxycytidine (DDC), a potent inhibitor of HIV replication, have been studied in rats. DDC was administered intravenously at doses of 10, 50, 100 and 200 mg kg-1. Plasma and urine drug concentrations were determined by HPLC. Non-compartmental pharmacokinetic parameters were calculated by area/moment analysis. DDC plasma concentrations declined rapidly with a terminal half-life of 0.98 +/- 0.18 h (mean +/- s.d.). No statistically significant differences were observed in pharmacokinetic parameters between the four doses. Total, renal and non-renal clearance values were independent of dose and averaged 1.67 +/- 0.24, 0.78 +/- 0.11, and 0.89 +/- 0.27 L h-1 kg-1, respectively. Approximately 50% of the dose was excreted unchanged in urine. Steady state volume of distribution was also independent of dose and averaged 1.2 +/- 0.21 L kg-1. Protein binding of DDC to rat serum proteins was independent of drug concentration with the fraction of drug bound averaging 0.45 +/- 0.12. Thus, the disposition pattern of DDC in the rat is independent of the administered dose even at high doses. Significant interspecies correlations were found for total, renal and non-renal clearance and steady state volume of distribution. Interspecies scaling resulted in superimposable plasma DDC concentration-time profiles from four laboratory animal species and man. Thus, plasma DDC concentrations in humans can be predicted from pharmacokinetic parameters obtained in laboratory animals.     

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

Summary Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method.Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours.We found a linear relationship (r=0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.     

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects

Summary Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H₂-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study.No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r=0.983). The apparent plasma clearance was 38.11·h^–1, 31.01·h^–1, and 47.41·h^–1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion.The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H₂-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.     

Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs

The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P > 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.     

Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part III: Pharmacokinetics, metabolism, dose dependency and gender effect after single or repeated administration to human healthy volunteers.

A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4- ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2), with a piperidinic structure, showing anti-histaminic properties was studied after administration to healthy human volunteers. The focus was on the pharmacokinetics, the metabolism, the dose dependency and gender differences of the pharmacokinetic parameters of BM 113 and its main desacetylated metabolite, BM 212. Unchanged BM 113 was not recovered in plasma or in urine. The elimination of the radioactivity was essentially urinary with about 81% recovered within 24 h. The elimination was completed with 97% of the administered dose recovered after 120 h. HPLC dosage of BM 212, using a specific method, showed that BM 212 represented 62% of the urine radioactivity. The plasma profile of radioactivity was characterized by two decreasing phases with respective half-lives of 3.71 +/- 0.66 h and 24.67 +/- 25.01 h. A dose dependency study realised with 20, 40, 60 and 80 mg oral doses administered to 8 healthy volunteers has proven the linearity of the pharmacokinetics of BM 212 in the studied range. BM 212 disposition after single and repeated BM 113 oral doses in a 14-day study did not vary and permitted to conclude that no auto-induction or auto-inhibition phenomenon was involved. No significant difference between men and women was observed. The concentration profile was mono or biexponential, depending on the subject but whatever the gender. An inter-individual variability appeared for both sexes and caused some variations in the pharmacokinetic parameters.     

Pharmacokinetic variability and strategy for therapeutic drug monitoring of saquinavir (SQV) in HIV-1 infected individuals

AIMS: To investigate the pharmacokinetic profile of the protease inhibitor saquinavir (SQV) after multiple doses in HIV-positive patients and to evaluate the possibility of predicting total body exposure of SQV from concentrations determined at single time points. METHODS: Twenty HIV-positive patients on steady-state treatment with SQV (Hard-Gel-Capsule, Invirase(R)) were enrolled in this study. Serial blood samples were obtained during a dosing interval. SQV plasma concentrations were determined by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were determined by noncompartmental techniques. RESULTS: There was a marked interindividual variability in SQV pharmacokinetic parameters with a 11-fold variability in total systemic exposure to SQV, as expressed by AUC(0,8h) values (range: 268-3009 ng ml-1 h, CV: 69%). The oral clearance shows an interindividual CV of 75%. A strong correlation (r=0.94) was found between SQV plasma concentration at 3 h (C3 h ) and AUC(0,8h). CONCLUSIONS: This study shows that C3 h is a good predictor for total body exposure of SQV and might be useful to predict SQV disposition in HIV-positive patients on steady-state treatment.     

Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside phosphorylase inhibitor, following single and multiple oral doses in healthy volunteers

The pharmacokinetic parameters of peldesine (BCX-34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally. Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high-pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics indicated that steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h, respectively.     

A systematic review on pharmacokinetic changes in critically ill patients: role of extracorporeal membrane oxygenation

Objective

Several factors including disease condition and different procedures could alter pharmacokinetic profile of drugs in critically ill patients. For optimizing patient''s outcome, changing in dosing regimen is necessary. Extracorporeal Membrane Oxygenation (ECMO) is one of the procedures which could change pharmacokinetic parameters.The aim of this review was to evaluate the effect of ECMO support on pharmacokinetic parameters and subsequently pharmacotherapy.

Method

A systematic review was conducted by reviewing all papers found by searching following key words; extracorporeal membrane oxygenation, ECMO, pharmacokinetic and pharmacotherapy in bibliography database.

Results

Different drug classes have been studied; mostly antibiotics. Almost all of the studies have been performed in neonates (as a case series). ECMO support is associated with altered pharmacokinetic parameters that may result in acute changes in plasma concentrations with potentially unpredictable pharmacological effect. Altreation in volume of distribution, protein binding, renal or hepatic clearance and sequestration of drugs by ECMO circuit may result in higher or lower doses requirement during ECMO. As yet, definite dosing guideline is not available.ECMO is extensively used recently for therapy and as a procedure affects pharmacokinetics profile along with other factors in critically ill patients. For optimizing the pharmacodynamic response and outcome of patients, drug regimen should be individualized through therapeutic drug monitoring whenever possible.     

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.     

Comparison of the clinical pharmacokinetics and concentration-effect relationships for medroxalol and labetalol.

The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half-life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2-3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration-hypotensive effect relationship was described for each drug.     

Single dose kinetics of thioridazine and its two psychoactive metabolites in healthy humans: a dose proportionality study

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression

The pharmacokinetics of hydrocortisone were examined following single intravenous doses of 5, 10, 20, and 40 mg hydrocortisone, as the sodium succinate salt, to healthy male volunteers. Endogenous hydrocortisone was suppressed by administration of 2 mg dexamethasone the night before hydrocortisone injection. Plasma samples obtained serially during 8 h after hydrocortisone injection were assayed by reversephase HPLC using a fixed wavelength (254 nm) ultraviolet detector. Initial concentrations of hydrocortisone in plasma were proportional to dose size. The subsequent decline in hydrocortisone concentrations was biphasic, and individual data sets were adequately described in terms of the pharmacokinetic two-compartment open model. Values of pharmacokinetic parameters were similar from the 5, 10, and 20 mg doses. Following the 40 mg dose, the overall elimination rate constant decreased, while the distribution volume, V_dss,and plasma clearance increased, in comparison with the values obtained from lower doses. Changes in the pharmacokinetics of hydrocortisone at high doses may be related to drug concentrationdependent changes in the binding of hydrocortisone to plasma proteins. Previously reported dosedependent changes in some pharmacokinetic parameters following oral hydrocortisone are attributed to absorption rather than distribution or elimination effects.     

Pharmacokinetics of alpha-dihydroergokryptine in monkeys after oral administration.

The pharmacokinetic profile of a single dose (6 mg/kg) of alpha-dihydroergokryptine (alpha-DHEK) was established after oral administration in monkeys using a radio-immunoassay technique for non-metabolized drug. alpha-DHEK showed a plasma profile according to an open three-compartment pharmacokinetic model with a long half-life (mean = 5.787 h). The disposition of alpha-DHEK involves a fast absorption, a slow distribution phase and a slow elimination phase. alpha-DHEK showed an high total clearance and distribution volume; the drug is largely metabolized, as concluded from the very low urinary excretion.     

Pharmacokinetic and pharmacodynamic studies with prazosin in chronic heart failure

The correlation between the plasma concentration of prazosin and the effects on supine and standing systemic blood pressure and heart rate was examined at 1/2, 1, 2, 4, and 8 hr after single oral doses of 0.5, 1, 2, and 4 mg in 8 patients with severe refractory heart failure due to coronary heart disease. Despite wide between-patient and within-patient variation in the plasma concentration, the grouped results showed a significant linear relationship between dose, peak concentration, and area under the time-concentration curve. Time of maximum plasma concentration (2 hr) and half-life in plasma (5.6 hr) were similar after all four doses. Compared to the reported pharmacokinetic profile of the drug in normal subjects, the plasma clearance of the drug in these patients in heart failure was substantially reduced. In the recumbent posture there were reductions in systolic and diastolic blood pressure without consistent changes in heart rate after all doses of prazosin. A clear dose-response effect of the drug on both variables only became apparent during standing, when there was a significant correlation between dose, the postural fall in systolic and diastolic blood pressure, and the increase in heart rate. Three of the 8 patients were unable to tolerate more than 1 mg prazosin due to postural hypotension.     

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.