The bioavailability and pharmacokinetics of guanfacine after oral and intravenous administration to healthy volunteers

Guanfacine is a centrally acting alpha-2 adrenergic agonist. The absolute bioavailability, pharmacokinetics, and renal clearance of this antihypertensive drug were investigated in healthy male volunteers. Eighteen subjects received a single oral or intravenous dose of guanfacine 3 mg in a two-way cross-over study design. Blood samples were obtained before dosing and up to 72 hours after dosing for determination of drug levels in plasma. Additional blood samples were obtained for protein binding studies. Urine was collected and pooled for specific intervals up to 96 hours after dosing. The absolute bioavailability of guanfacine after a single oral dose was 81.1%. The elimination half-lives were 13.8 hours and 13.4 hours after oral and intravenous administration, respectively. The volume of distribution results were approximately 6 L/kg by both routes of administration. The mean plasma protein binding results were 71.6%, not influenced by plasma concentration or route of administration. The urinary recovery of guanfacine was 44.3% after oral dosing and 50% after intravenous dosing. Renal clearance of guanfacine was 50% of total body clearance and appeared to be due to a net renal tubular secretory process.     

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

After oral administration of 100 mg dapsone (DDS) to 25 healthy volunteers peak serum DDS concentrations between 1.10 and 2.33 mg l-1 were reached within 0.5 to 4 h. AUCs varied from 20.3 to 75.4 mg l-1 h, while the elimination half-lives ranged from 11.5 to 29.2 h. The apparent volumes of distribution were 0.84 to 1.26 l kg-1 body weight, assuming complete bioavailability. Statistically significant differences in peak drug concentration, peak time and AUC existed between males and females. Absorption and elimination of DDS appeared to be faster than reported in other studies, suggesting differences in DDS kinetics between healthy volunteers and patients.     

The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers.

The pharmacokinetics of nalbuphine were studied in 10 healthy volunteers on two separate occasions following administration by either the intravenous (20 mg) or oral (60 mg) route. After administration, serum concentrations of nalbuphine were measured for 12 h using a high pressure liquid chromatography assay, and pharmacokinetic parameters were derived using a three compartment model. After i.v. administration, elimination half-life was 222 (111-460) min (mean and range) and total body clearance was 1.5 (0.8-2.3) 1 min-1.Cmax after oral administration was 21.4 (6.0-36.2) ng ml-1 and tmax was 46.6 (15.3-89.0) min. Bioavailability of the oral preparation was 11.8 (6.1-20.1)%.     

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.     

The pharmacokinetics of oral and intravenous prenalterol in young, healthy volunteers

The pharmacokinetics of prenalterol in healthy young volunteers after i.v. and oral dosing has been studied. There is evidence of non-linearity following the i.v. dosing. Evidence of dose-dependent pharmacokinetics following i.v. dosing has been obtained. The sustained-release formulation is very effective: almost 12 h were needed to achieve 50 per cent of the total AUC.     

The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers

The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing.The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l^–1 and t1/2_z increased to 4.0 h (NS).There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.     

The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five-week period, subjects received single doses of each of four different formulations of nalbuphine, with a one-week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half-life of nalbuphine with this route of administration was 2.3 hours. In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half-lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmax and AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half-life of nalbuphine associated with oral administration are likely due to extensive first-pass metabolism and enterohepatic circulation, respectively.     

Absolute bioavailability of paracetamol after oral or rectal administration in healthy volunteers

The absolute bioavailability of paracetamol (Tachipirina) administered in single doses orally and rectally was studied in nine healthy adult volunteers. The results of the rapid intravenous injection of 600 mg show that the kinetics of paracetamol can be represented by an open two-compartment model with introduction and elimination occurring in the central compartment. The oral administration shows an absolute bioavailability of 60-70% independent of the pharmaceutical form and gastric contents. The rectal administration shows a lower absolute bioavailability (of about 30-40%) substantially independent of dose in the range under consideration. The pharmaceutical form, food and the route of administration modify the plasma concentration-time curves of free paracetamol and of its main metabolites. A moderate inter-individual variation in the kinetics and the bioavailability was observed.     

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.     

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 bioavailability study of two ibuprofen preparations after oral administration in healthy volunteers

The bioavailability of a new ibuprofen (2-(p-isobutylphenyl)propionic acid, CAS 15687-27-1) preparation was compared with a reference preparation of the drug in 23 healthy male volunteers, aged between 19 and 27. A single dose of 400 mg was given orally in the fasted state, using a randomized two-way crossover study. A washout period of two weeks separated both treatment periods. Ibuprofen plasma levels were determined by means of a validated HPLC method (UV detector). Values of 154.48 +/- 53.27 microg x h/ml (95 % confidence interval CI: 133.50-177.03) for the test, and 140.86 +/- 44.82 microg x h/ml (95% CI: 122.53-159.16) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum plasma concentrations Cmax of 39.53 +/- 7.11 microg/ml (95 % CI: 35.97-41.78) and 37.71 +/- 8.67 microg/ml (95% CI: 33.37-40.46) achieved for the test and reference preparations did not differ significantly. AUC(0-infinity) and Cmax ratios (90% CI) were within the 80-125% interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new ibuprofen preparation is therapeutically equivalent to the reference preparation for both, the extent and the rate of absorption, after single dose administration in healthy volunteers.     

Comparative bioavailability of metoprolol tartrate after oral and transdermal administration in healthy male volunteers

BACKGROUND AND OBJECTIVE: Transdermal drug delivery systems (TDDSs) of metoprolol tartrate have been previously prepared and evaluated in vitro and in vivo in an animal model. This study compares the bioavailability of metoprolol tartrate from a TDDS with that from a conventional marketed tablet in healthy human volunteers. METHODS: This was an open-label, balanced randomised, two-treatment, two-period crossover study with a washout period of 1 week. Volunteers were randomised (by means of a SAS software-generated randomisation schedule) to have a TDDS applied to their chest for 48 hours or to receive a 100 mg conventional marketed tablet of metoprolol tartrate in period I. In period II, the volunteers received the other dosage form. Blood samples were collected through an indwelling cannula placed in the forearm vein of each subject. Metoprolol tartrate concentrations were quantified in plasma samples by a validated high-performance liquid chromatography method. RESULTS: A 3-fold improvement in bioavailability was observed with the TDDS form over oral therapy as shown by the extent of absorption indicated by the mean area under the concentration-time curve from time zero to time t values for tablets (451.98 ng x h/mL) and TDDS (1552.66 ng x h/mL). Although the maximum plasma concentration was higher for the tablet form than the TDDS (77.67 +/- 23.33 vs 51.16 +/- 16.61 ng/mL), the variable absorption profile, which is a characteristic feature of oral therapy, was quite evident. Plasma metoprolol tartrate concentrations plummeted to therapeutically ineffective concentrations as early as 8 hours following oral administration. CONCLUSION: The TDDS developed in our laboratory produced therapeutically effective plasma concentrations for up to 48 hours, with a minimum of 26.09 ng/mL and a maximum of 76.70 ng/mL, which is in good agreement with the therapeutic range (20-100 ng/mL) of metoprolol tartrate. It could be concluded that the TDDS meets the intended goal of 2-day management of hypertension with application of a single patch, obviating the inconvenience of frequent administration and thus improving patient compliance.     

国产氧氟沙星在健康成人中的药物动力学和生物利用度研究

本文采用专一性强、灵敏度高的HPLC 荧光检测法,测定氧氟沙星血、尿浓度。对国产氧氟沙星片在12例健康受试者中进行药物动力学和生物利用度研究。氧氟沙星片口服给药多数人为一房室模型,其主要药动学参数,国产片和进口片分别为:T_(1/2)6.2±1.3和6.1±1.5h;Vd 1.5±0.4和1.6±0.5l/kg;C_(max)8.6±2.5umol/L 和7.9±1.4μmol/L;T_(max)0.6±0.5和0.6±1.0h;Cl_T13±4和12±4 l/min;AUC_(o-∞)76±23和73±21μmol/L·h。其相对生物利用度为104.9±9.9%。     

Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid/eicosapentaenoic acid after multiple-dose administration in healthy volunteers

Objectives  To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference formulation in healthy subjects. Methods  Forty-eight healthy subjects received a 28-day oral treatment with DHA/EPA in the form of either the test or the reference product according to an open-label, randomized, parallel-group design. Both formulations were given t.i.d. at 8-h intervals at a dose of 3.0 g/day. Steady-state DHA and EPA concentrations in plasma and lysed whole blood were measured by gas-liquid chromatography at baseline and after 7, 14, 21 and 28 days of treatment. Kinetic parameters were compared both after subtraction of baseline concentrations and by using baseline concentrations as a covariate. Results  For both DHA and EPA, plasma and RBC concentrations measured from day 7 to day 28 were significantly higher than at baseline and did not differ significantly between the two products. On day 28 the plasma DHA concentration on average doubled the baseline level after administration of test and reference product, while there was a 10-fold increase in EPA plasma concentration. When the assessment was performed using baseline values as covariate, test-to-reference ratios for area under the curve (AUCss_0–8) and for peak concentration (Css_max) after the last administration on day 28 met bioequivalence criteria (i.e., 90% confidence intervals within 0.80–1.25 for AUCss_0–8 ratios, and within 0.75–1.33 for Css_max ratios). When the assessment was conducted after subtraction of baseline values, the 90% confidence intervals for Css_max ratios were within the bioequivalence range, whereas the intervals for AUCss_0–8 ratio were borderline for bioequivalence. Conclusion  The two formulations tested were similarly effective in increasing DHA and EPA concentrations in plasma and lysed whole blood, and showed comparable bioavailability for both active components.     

The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.     

Plasma pharmacokinetics of cinmetacin following oral administration in healthy volunteers

The pharmacokinetics of a single 600 mg oral dose of 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid (cinmetacin, Cindomet) was studied in 8 healthy volunteers of both sexes. Plasma levels of the drug were assayed by using an HPLC technique ad hoc devised. Following administration, the Cmax was reached at the 2nd h in 7 out of 8 subjects with an average value of 18.19 micrograms/ml; 12 h after the dose (last sampling time) appreciable plasma levels of cinmetacin were measured, corresponding to 17.2% of the maximum average concentration. The mean values +/- S.E. concerning the elimination half-life, the total volume of distribution, the total plasma clearance and the total area under the curve were 3.80 +/- 0.21 h, 0.28 +/- 0.03 l/kg, 0.051 +/- 0.005 l/kg/h, and 125.64 +/- 15.97 micrograms.h/ml, respectively. The plasma decay of cinmetacin was monophasic and the data were interpreted according to a one-compartment open model. Overall results indicate that cinmetacin is well and rapidly absorbed orally and widely distributed in body fluids.     

单剂量口服曲昔匹特胶囊的相对生物利用度及生物等效性

目的 研究曲昔匹特胶囊的药代动力学特征及生物等效性。方法 18名健康男性志愿者随机双交叉给药,分别单剂量口服100mg的曲昔匹特胶囊试验药和片剂对照药,用血浆碱化、液相萃取提取和反相高效液相色谱法测定血药浓度,计算两者的药代动力学参数及相对生物利用度。结果 口服曲昔匹特胶囊100mg试验药及片剂对照药的主要药代动力学参数t_(1/2ke)分别为6.52±1.62和7.03±2.27h;t_(max)分别为2.89±0.93和2.97±1.25h,C_(max)分别为0.98±0.27和1.06±0.31mg·L~(-1),AUC_(0-24)分别为15.18±4.11和15.96±3.97mg·h·L~(-1),AUC_(0-∞)分别为15.83±4.12和16.82±4.47 mg·h·L~(-1)相对生物利用度为(95.72±14.92)％。结论 试验药曲昔匹特胶囊和对照药曲昔匹特片剂具有生物等效性。     

Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.

In a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt tablets containing 250 mg alpha-methyldopa (AMD) and Presinol film tablets with identical active ingredient content was examined in 24 healthy volunteers. Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) were evaluated statistically. Wilcoxon's nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0-infinity at the 90% probability level, the confidence interval was 0.883-1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt and Presinol tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt (test preparation) and Presinol (reference preparation) calculated from the AUC0-infinity values was 116.7+/-56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt and Presinol can be considered as bioequivalent preparations.     

Comparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P<10(-4) and intravenously: 15.0+/-2.4 versus 5.1+/-0.6 hr, P<10(-4)). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0-->24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.