Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p < 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2'R, 2R)- and (2'S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.     

Furosemide pharmacokinetics and pharmacodynamics following gastroretentive dosage form administration to healthy volunteers

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage from (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate-release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled-release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.     

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.     

A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.     

Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400 mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases (p < 0.05) in C_max, T_max, AUC_T and elimination half-life (T_1/2β) of proguanil compared with values for proguanil alone [C_max: 2.55 ± 0.24 mg/l vs 3.75 ± 0.48 mg/l; T_max: 2.80 ± 0.99 h vs 4.80 ± 0.99 h; AUC_T: 45.58 ± 12.75 mg h/l vs 97.00 ± 23.33 mg h/l; T_1/2β: 16.50 ± 4.55 h vs 23.24 ± 4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease (p < 0.05) in C_max and AUC of the metabolite.These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels.     

The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the racemate.

A single dose of racemic ketorolac (30 mg of tromethamine salt, Toradol) was administered by bolus intramuscular injection to four young, healthy volunteers. The concentrations of total (bound plus unbound) (R)- and (S)-ketorolac were measured in plasma for 9 h after dosing. The mean +/- s.d. clearance of (S)-ketorolac (45.9 +/- 10.1 ml h-1 kg-1) exceeded (P = 0.0032) that of the (R)-enantiomer (19.0 +/- 5.0 ml h-1 kg-1). The mean +/- s.d. AUC ratio for (S)-ketorolac:(R)-ketorolac (0.442 +/- 0.043) was significantly different from unity (P = 0.0001). The steady-state volume of distribution of (S)-ketorolac (0.135 +/- 0.022 l kg-1) was significantly different (P = 0.0013) from that of its optical antipode (0.075 +/- 0.014 l kg-1) and the half-lives of (S)- and (R)-ketorolac (2.35 +/- 0.23 h and 3.62 +/- 0.79 h, respectively) were also significantly different (P = 0.026). These data indicate that the disposition of ketorolac in man is subject to marked enantioselectivity and, because of possible differences in biological activity of (S)- and (R)-ketorolac, emphasize the need to monitor separate stereoisomer concentrations of the drug if pharmacological data are to be interpreted correctly.     

Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyloxybutynin following oral and transdermal administration of the racemate in healthy volunteers

Purpose. To characterize the enantiomers of oxybutynin (OXY) and N-desethyloxybutynin (DEO) following transdermal and oral administration. Methods. OXY was administered either as a single transdermal system over a 96 h wear period or as a single 5 mg immediate-release tablet to 18 healthy male and female subjects in a randomized, open-label, two-way crossover design. Blood samples were collected for 108 h after application of the transdermal system and for 6 h after oral administration. Plasma concentrations of the R- and S-enantiomers of OXY and DEO were assayed by LC-MS/MS. Enantiomer in vitro skin flux was evaluated using human cadaver skin.Results. In vitro skin flux studies demonstrated equal absorption of R and S- OXY. Plasma concentrations and pharmacokinetic parameters of the R-enantiomers of OXY and DEO were slightly lower than the S-enantiomers following transdermal OXY. The relative AUC values were S-OXY>S-DEO>R-OXY>R-DEO. The AUC ratios of DEO/OXY were less than 1 for both the R- and S- enantiomers. Following oral dosing, plasma DEO concentrations greatly exceeded OXY resulting in relative AUC values of R-DEO>S-DEO>S-OXY>R-OXY. The mean AUC ratios of S- and R-DEO/OXY were 3.25 and 8.93, respectively. Conclusions. Stereoselective metabolism of OXY was evident following both transdermal and oral administration of OXY. The reduced pre-systemic metabolism of transdermally administered OXY compared to oral administration resulted in not only significantly lower DEO plasma concentrations, but also a different metabolite pattern. The differences between R-OXY and R-DEO following the two routes of administration support the potential for comparable clinical efficacy and reduced anticholinergic side-effects with transdermal treatment.     

Chiral separation of ibuprofen and chiral pharmacokinetics in healthy Chinese volunteers.

A rapid, sensitive and stereoselective HPLC method based on chiral column analysis was developed and fully validated for the simultaneous determination of the two enantiomers of ibuprofen in human plasma. Using this method, a chiral pharmacokinetic study of two different ibuprofen tablets, i.e. dexibuprofen tablets and racemic ibuprofen tablets, was carried out on 20 healthy Chinese male volunteers according to a single-dose (400 mg), two-way, cross-over randomized design. When a 'non-chiral calculation method' was used, the statistical analysis showed no significant difference for the pharmacokinetic parameters (AUC0-infinity, AUC0-t, Cmax and tmax) between the two oral formulations, suggesting that they were pharmaceutically bioequivalent. Considering that the pharmacological activity of ibuprofen resides exclusively in the S(+)-enantiomer, and that the unidirectional inversion of the R(-) to the S(+)-enantiomer is incomplete and might be race-dependent, the pharmacokinetic parameters for only the S(+)-enantiomer were further compared and the inversion ratio calculated. It was found that only 25% of R(-)-ibuprofen in the racemic ibuprofen tablets was inverted into S(+)-ibuprofen in the Chinese population, which suggested that dexibuprofen might possess a much stronger pharmacological activity than that of racemic ibuprofen when administered at the same dose.     

Clinical pharmacokinetics and metabolism of pyrazinamide in healthy volunteers

Eight healthy volunteers were treated with a single dose of pyrazinamide 35 mg/kg. The aim of the study was to evaluate the pharmacokinetic profile of the product and of its metabolites. Urine and blood samples were collected till the 60th h. The kinetics of pyrazinamide could be characterized as follows: CPmax = 50.1 micrograms/ml, tmax less than 1 h, t1/2 alpha = 3.2 h, t1/2 beta = 23 h, U(0-60 h) = 1.6% of the dose administered. The kinetics of the main metabolite, the pyrazinoic acid, gave the following values: CPmax = 66.6 micrograms/ml, tmax = 4 h, t1/2 beta = 12.3 h, U(0-60 h) = 37.5%, of the administered dose.     

Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers

Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US-FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double-blind, parallel-group design. Healthy male and female volunteers (n = 22-23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng.h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 micrograms for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.     

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.     

A comparative study of the pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers

OBJECTIVE: Ibuprofen arginate is a salt formulation of ibuprofen designed to reach target concentrations rapidly. The primary objective of this study was to compare the 12-h pharmacokinetic profile of S(+)-ibuprofen following administration of single doses of ibuprofen arginate (600 mg) and dexibuprofen (400 mg) in healthy volunteers. METHODS: Twenty-four volunteers were recruited into an open-label, randomised, two-period, single-centre study with crossover design. RESULTS: Both treatments were well tolerated. Ibuprofen arginate and dexibuprofen showed similar bioavailability for S(+)-ibuprofen. Compared with dexibuprofen, ibuprofen arginate demonstrated a 45% higher maximum concentration (C(max)), and a time to peak concentration (T(max)) 2 h sooner. CONCLUSION: Ibuprofen arginate approaches maximum concentrations of S(+)-ibuprofen faster and higher than dexibuprofen.     

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.     

Disposition,metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration

Abstract

1. The pharmacokinetics and disposition of delafloxacin was investigated following a single intravenous (300?mg, 100?µCi) dose to healthy male subjects.

2. Mean C_max, AUC_0–∞, T_max and t_1/2 values for delafloxacin were 8.98?µg/mL, 21.31?µg?h/mL, 1?h and 2.35?h, respectively, after intravenous dosing.

3. Radioactivity was predominantly excreted via the kidney with 66% of the radioactive dose recovered in the urine. Approximately 29% of the radioactivity was recovered in the faeces, giving an overall mean recovery of 94% administered radioactivity.

4. The predominant circulating components were identified as delafloxacin and a direct glucuronide conjugate of delafloxacin.     

N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10–50 mg oral doses in healthy volunteers

Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-desmethyladinazolam pharmacokinetics were dose independent over this range. Doserelated performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC₅₀ of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.     

Plasma pharmacokinetics of desmopressin following sublingual administration: an exploratory dose-escalation study in healthy male volunteers

OBJECTIVE: Desmopressin is usually administered intranasally in the treatment of central diabetes insipidus or nocturnal enuresis. The sublingual administration of desmopressin is expected to be an alternative to the intranasal route with advantages to children and to patients with allergic rhinitis or chronic rhinosinusitis. Therefore, the present study was carried out to explore the time-versus-concentration profile of desmopressin in plasma after sublingual administration to healthy volunteers. SUBJECTS AND METHODS: A total of 16 healthy male volunteers were enrolled in this open, exploratory, 1-period, randomized, dose-escalation study. Volunteers received a single sublingual dose of either 20, 40, 80, 160, 240 or 320 microg of desmopressin acetate. Desmopressin plasma concentrations were measured over a 12-hour period using a validated radioimmunoassay method. Safety and tolerability were assessed simultaneously. RESULTS: Plasma concentrations of desmopressin were below the lower limit of quantification (LLOQ) of 5 pg/ml for doses lower than 80 microg. For the doses of 160 - 320 microg the time-versus-concentration profiles were higher than the LLOQ. The area under the curve from 0 - 12 h (AUC0-12h) was 54.66 +/- 25.92 pg x h/ml after the 160 microg dose, 104.38 +/- 79.10 pg x h/ml following the 240 microg dose and 133.18 +/- 181.84 pg x h/ml following the 320 microg dose. Given the data from previous experiments, the time-versus-concentration profile of desmopressin in plasma after a sublingual dose of 240 microg appeared to be in the range of previously published data on an intranasal dose of 20 microg. Sublingual administration of desmopressin proved to be safe and was well tolerated by all volunteers. CONCLUSION: A very high inter-individual variability in desmopressin plasma concentrations was detected after sublingual administration. A sublingual dose of 240 microg of desmopressin appeared to result in a pharmacokinetic profile comparable to 20 microg administered intranasally. These data, however, need to be verified in a separate well-designed prospective clinical study.     

吸入制剂人体药动学研究中关于给药的探讨

给药是药物临床试验中的关键环节，也是吸入制剂人体药动学研究中的难点之一。对吸入制剂给药环节中一些细节的把握可能直接影响制剂间生物等效性的建立，包括给药前准备、吸入技术培训、给药中及给药后处理等。本文将结合临床实践经验，针对吸入制剂人体药动学研究中的给药环节进行探讨并总结。     

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.     

Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry-powder inhaler (DPI) and the metered-dose inhaler with an alternate propellant (MDI-AP). The pharmacokinetics of single doses (400 micrograms) of MF administered by intravenous (i.v.) and inhalation routes was assessed in a randomized, three-way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H-) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following i.v. administration, MF was detected in all subjects for at least 8 hours postdose. The half-life (t1/2) following i.v. administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI-AP administration had plasma concentrations of MF above the LOQ indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of 3H-MF (200 microCi) by DPI revealed that much of the dose (approximately 41%) was excreted unchanged in the feces (0-72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.