Methylprednisolone pharmacokinetics after intravenous and oral administration.

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.     

Comparative pharmacokinetics of paracetamol in humans following single oral and rectal administration (author's transl)

The pharmacokinetic behaviour of N-acetyl-p-aminophenol (paracetamol) after single dose applications of 500 mg and 1000 mg dosages in the form of liquids, tablets and suppositories was compared. The estimation of the pharmacokinetic constants by a simultaneous curve fitting with a direct search procedure, based on an open two-compartment model, showed for the liquid as well as for the tablet formulation a good conformable and dosage proportional behaviour of the relative bioavailability. In opposite to the oral application, the suppositories had a significantly reduced invasion kinetics with a comparable elimination kinetics characterized by a lowering of Cmax and an increase of Tmax-values with comparable AUCs. The calculation of collapse-coefficients showed, with the exception of one suppository formulation, for all administrations a pharmacokinetic behaviour deviating from an open one-compartment model. The clinical consequences resulting from the pharmacokinetic behaviour of the different galenic formulations and routes of administrations are discussed.     

Biopharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal,oral, intramuscular and intravenous administration in man

Rectal absorption of diazepam was studied in man and compared with intravenous, intramuscular and oral administration. Plasma concentrations of diazeparn were measured by means of HPLC analysis after a single dose of 10 mg diazeparn in a cross-over study in 9 healthy volunteers.Plasma concentration—time curves following intravenous administration were described by a tri-exponential function consistent with a three-compartment model system. It was calculated that the drug will not exhibit measurable first pass metabolism.Comparing the absorption rate constants it appeared that rectal absorption of a solution of diazeparn proceeded significantly (I <0.05) more rapidly than absorption after oral and intramuscular administration. Absorption from a macrogol suppository dosage form was rather slow.The mechanism of the rapid rectal absorption of diazeparn from the solute state was discussed. No essential difference in bioavailability was observed between the intramuscular injection, rectal solution and tablets as compared with the intravenous injection. Only for the suppository dosage form was bioavailability calculated to be significantly lower.     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

The pharmacokinetics of oxycodone after intravenous injection in adults.

Oxycodone chloride (0.07 mg kg-1) was given by intravenous bolus to nine young adult surgical patients on the first postoperative day. Plasma was sampled for up to 12 h. Mean values of t1/2z, CL and Vss were 222 min, 0.78 l min-1 and 2.60 l kg-1, respectively. The concentrations of the metabolite noroxycodone was also measured. The mean AUC(0,12) ratio of noroxycodone to oxycodone was 0.33. Oxymorphone was not detected.     

The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

1. The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross-over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg-1) and twice orally (0.28 mg kg-1) at intervals of 2 weeks. A double-blind randomized pretreatment with amitriptyline (10-50 mg a day) or placebo was given prior to oral oxycodone. 2. The concentrations of oxycodone, noroxycodone and oxymorphone in plasma and the 24 h urine recoveries of their conjugated and unconjugated forms were measured by gas chromatography. 3. No differences were found between treatments in mean Cmax and AUC values of oxycodone which varied from 34 to 38 ng ml-1 and from 208 to 245 ng ml-1 h, respectively. The median tmax of oxycodone was 1 h in all groups. The bioavailability of oral relative to i.m. oxycodone was 60%. The mean renal clearance of oxycodone was 0.07-0.08 l min-1. The kinetics of oxycodone were unaffected by amitriptyline. 4. The mean ratio of the AUC(0.24 h) values of unconjugated noroxycodone to oxycodone was 0.45 after i.m. oxycodone and 0.6-0.8 after oral oxycodone. Plasma oxymorphone concentrations were below the limit of the assay. Eight to 14% of the dose of oxycodone was excreted in the urine as unconjugated and conjugated oxycodone over 24 h. Oxymorphone was excreted mainly as a conjugate whereas noroxycodone was recovered mostly in an unconjugated form.     

Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients.

1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15-90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml-1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10-20 mg of solution, and then usually after a delay of over 2 h.     

Comparative pharmacokinetics of sulphasalazine and sulphapyridine after rectal and oral administration to patients with ulcerative colitis

Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (C_max) of SASP and SP were significantly lower after rectal than oral administration of SASP (p<0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.     

The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers

The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set-up as a four-way cross-over design with a wash-out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Pharmacokinetics of ketotifen fumarate after intravenous,intranasal, oral and rectal administration in rabbits

The pharmacokinetics of ketotifen fumarate (KF) was examined after administration in rabbits through four different routes (intravenous, intranasal, oral and rectal). The time-course of the plasma concentration of KF after intravenous administration (1 mg/kg dose) fitted a two-compartment open model. KF was rapidly absorbed and showed a high plasma concentration within 0.33 h after intranasal administration. The absolute bioavailability of KF after intranasal administration was 66%. After oral administration at a dose of 1 mg/kg, the plasma concentration of KF was below the detection limit of HPLC analysis. Even at 5 mg/kg, the value of the area under the plasma concentration-time curve (AUC) after oral administration of KF was significantly lower than that after intranasal administration of 1 mg/kg. Oral bioavailability was only 8%. The very low bioavailability of KF after oral administration might be due to the first-pass effect in the liver. We also prepared suppositories containing KF (1 mg/kg) for rectal administration in rabbits. After rectal administration, KF was rapidly absorbed and its bioavailability was 34%. These results indicated that the intranasal route appears the most effective for administering KF, and that rectal administration may be superior to oral administration in terms of bioavailability.     

Dose-independent pharmacokinetics of torasemide after intravenous and oral administration to rats

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.     

The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers.

1. The absolute bioavailability of morphine from oral aqueous solution, a controlled release oral tablet (MST-Continus) and a controlled release buccal tablet has been investigated in six healthy volunteers. 2. Analysis of plasma samples for morphine and its active metabolite morphine-6-glucuronide (M6G) was by means of a differential radioimmunoassay technique. Absolute bioavailability for morphine was estimated to be 23.9% after oral solution, 22.4% after MST-Continus and 18.7% after the buccal tablet. Maximum plasma morphine concentrations were seen at 45 min (oral solution), 2.5 h (MST) and 6 h (buccal). 3. There was no difference in the amount of M6G appearing in plasma after intravenous, oral or buccal administration but the mean ratio of AUCs for M6G: morphine in plasma after intravenous morphine was 2 : 1 compared with 11 : 1 after oral and buccal morphine.     

Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats

The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.     

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and pharmacokinetics of naltrexone after intravenous and oral administration in rhesus monkeys

The purposes of this investigation were to determine the disposition of naltrexone (NTX) in monkeys and assess the role of first-pass metabolism and enterohepatic cycling in the disposition process. Concentrations of naltrexone and three metabolites were determined in plasma and urine as a function of time after po and iv NTX administration in six monkeys. Urinary recovery of NTX and metabolites 0-48 hr after iv administration (10 mg/kg) totaled 52% of the dose. Recovery in feces was minimal. Total urinary excretion of NTX and metabolites after po administration was 89% of that after iv administration, suggestive of good absorption of NTX from solution. However, the area under the plasma level-time curve for NTX after po administration was only 3.6% of that after iv administration, indicating a very high first-pass effect. The calculated extraction ratio was 0.96-0.99. Analysis of plasma level-time and urinary excretion rate-time data for NTX, conjugated NTX, beta-naltrexol, and conjugated beta-naltrexol after iv administration revealed that 1) the decline of plasma levels or urinary excretion rates with time for the conjugated metabolites was parallel to the decline for the apparent precursor; 2) the decline of plasma levels or urinary excretion rates for beta-naltrexol was slower than for naltrexone; and 3) there is evidence for a pronounced enterohepatic cycling of conjugated NTX and conjugated beta-naltrexol that influences the plasma level-time profile of these conjugates and the unconjugated compounds as well.     

Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans

Objective: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM).

Methods: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, ¹H NMR, and ¹³C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets.

Results: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. C_max, T_max and AUC_0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC_0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points.

Conclusion: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.     

Pharmacokinetics and bioavailability of intravenous,oral, and rectal nitrazepam in humans

The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.