Biomedical subjects

R Bonn

Publications and source records attributed to R Bonn.

At least 19 recordsLinked to original sources

PubMed2000

Comparison of the initial hemodynamic effects of immediate-release versus sustained-release isosorbide-5-mononitrate following single oral doses.

In this double-blind, randomized, placebo-controlled cross-over study, the authors investigated the initial time course of effects of isosorbide-5-mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate-release formulation (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b-ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate-release or the sustained-release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS-5-MN following both formulations. Thus, the administration of the sustained-release formulation of IS-5-MN 50 mg caused similar maximum effects when compared with an immediate-release formulation (20 mg). While the onset of effect of IS-5-MN on the a/b-ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate- or the sustained-release formulation, the onset of effect of the sustained-release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.

Adult↗

PubMed1996

Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide.

OBJECTIVE: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. METHODS: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. RESULTS: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(O-t), the study showed a mean value of moexipril 437 ng.ml-1.h-1 following administration of moexipril alone and 416 ng.ml-1.h-1 following moexipril concomitantly with hydrochlorothiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng.ml-1.h-1, respectively. The Cmax of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng.ml-1 after administration of moexipril alone and 241.0 (69.2) ng.ml-1 after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) micrograms. CONCLUSIONS: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide.

Adult↗

PubMed1995

Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Prostaglandin E1 (PGE1) (30, 60, 120 micrograms) was administered by intravenous infusion over a 120 min period in an open, three way randomized, cross-over study to 12 healthy male volunteers. For the evaluation of PGE1, PGE0 and 15-keto-PGE0, blood samples were drawn prior to, during and after the infusion. Analytical measurements were performed by gas chromatography/negative ion chemical ionization triple stage quadruple mass spectrometry, a highly specific and sensitive GC/MS/MS-method. During intravenous infusion of 30, 60 and 120 micrograms PGE1, endogenous plasma PGE1 concentrations increased from 1.7 +/- 0.8 to 4.2 +/- 1.1, 6.7 +/- 1.0 and 11.0 +/- 1.9 pg ml-1 respectively. PGE0 plasma concentrations increased from endogenous levels of 1.3 +/- 1.0 pg ml-1 to 7.6 +/- 2.1, 14.1 +/- 3.7 and 28.0 +/- 3.0 pg ml-1 respectively, whilst 15-keto-PGE0 plasma concentrations increased from endogenous levels of 10.2 +/- 13.9 pg ml-1 to 99.3 +/- 27.9, 190.4 +/- 52.5 and 357.2 +/- 72.6 pg ml-1 respectively. Within the dose range of 30-120 micrograms PGE1 2 h-1 there was a linear increase of Cmax and AUC with the dose. The results of the analysis of variance after baseline and dose-correction show a 90% confidence interval in the bioequivalence acceptance range of 80 to 125%.

Adult↗

PubMed1995

Evaluation of the pharmacokinetics and absolute bioavailability of three isosorbide-5-mononitrate preparations in healthy volunteers.

The objective of this study was two-fold: 1. to determine the pharmacokinetic parameters and the bioavailability of two 20 mg isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) preparations (treatments A and B) after single oral administration and 2. to evaluate the absolute bioavailability of IS-5-MN, which was possible by the administration of a third IS-5-MN preparation (treatment C) by the intravenous route (1 mg/ml, dose 20 mg). The three preparations were examined in 24 healthy volunteers according to a randomized 3-way cross-over design, blood samples were withdrawn up to 24 h following the administration of IS-5-MN and plasma concentrations of IS-5-MN were quantified by a gas chromatography method. The two oral preparations led to peak concentration values of about 360 ng/ml of IS-5-MN in the mean 0.90 h (treatment A) and 0.97 h (treatment B) after drug administration. The corresponding values for the infusion were 339.6 ng/ml and 2.59 h in the mean. For the areas under the curve (AUC(0-infinity)) mean values of 2733 (treatment A). 2724 (treatment B) and 2877 h x ng/ml (treatment C) were found. The absolute bioavailability of both oral treatments revealed values of 95.00% and 94.74% for treatments A and B, respectively. The statistical comparison (ANOVA, confidence intervals) of the pharmacokinetic parameters showed bioequivalence between both oral preparations and equivalence in the amount of drug absorption between both oral formulations and the i.v.-infusion. The observed undesired side effects (e.g. headache or nausea) are well known to occur after IS-5-MN administration.

Administration, Oral↗

PubMed1994

Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects.

In a single-blind, randomized, two-way cross-over study with 12 healthy male volunteers, 60 micrograms of prostaglandin E1 (PGE1) or placebo was administered by intravenous infusion during a 120-min period. PGE1, 13,14-dihydro-PGE1 (PGE0) and 15-keto-PGE0 plasma concentrations were measured by a highly specific and sensitive GC-MS/MS method. Endogenous PGE1 plasma concentrations ranged between 1.2 and 1.8 pg.ml-1. Endogenous PGE0 and 15-keto-PGE0 plasma concentrations varied from 0.8 to 1.3 pg.ml-1 and from 4.2 to 6.0 pg/ml respectively. During intravenous infusion of PGE1, plasma PGE1 concentrations rose to a level twice as high as during the placebo infusion. In contrast, PGE0 plasma concentrations were 8 times higher during PGE1 infusion than during placebo infusion, and 15-keto-PGE0 plasma concentrations were 20 times higher. The new analytical method has thus been useful to describe the pharmacokinetics of PGE1 and its metabolites PGE0 and 15-keto-PGE0, during and after intravenous infusion of PGE1.

Adult↗

PubMed1994

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration.

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers. After the sublingual spray Cmax was higher (39.0 ng.ml-1) and tmax was shorter (3.9 min) than after the sublingual (22.8 ng.ml-1 and 13.8 min) and peroral (16.9 ng.ml-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng.ml-1.min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively. The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v. administration to man (12-h infusion), and to rat and dog (bolus injection). 2. Renal excretion (mainly in 24 h) accounted for at least 80% dose in all three species, and the only two important metabolites were identified as 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and 4-guanidinobenzoic acid (GBA). 3. Parent drug was not detected in human plasma either during or after infusion of 14C-camostat mesylate owing to rapid hydrolysis of the side-chain ester group (t1/2 < 1 min). Steady-state levels of both GBPA and GBA in plasma were apparently attained by the end of the infusion period. Mean terminal half-life, systemic clearance and apparent volume of distribution at steady-state of GBPA in man were 1.0 h, 6.4 ml/min per kg and 0.38 l/kg, respectively, and the corresponding values for GBA were 2.4 h, 4.7 ml/min per kg and 1.01/kg respectively. 4. Radioactivity was rapidly distributed to most tissues after bolus i.v. doses of 14C-camostat mesylate to rats and dogs, with highest levels being associated with the liver and kidney, the two main organs of drug elimination. Concentrations in the pancreas, a possible site for drug action, were generally lower than those in plasma.

Adult↗

PubMed1994

Bioequivalence evaluation of two glyceryl trinitrate patches after 12-h usage in healthy volunteers.

The study objective was to determine the bioavailability and main pharmacokinetic parameters of glyceryl trinitrate (GTN, CAS 55-63-0) following cutaneous application of two different glyceryl trinitrate patches using a randomized cross-over design. The two patches investigated were Deponit 5 (a newly developed test patch) and an already marketed reference patch. Thirty-seven healthy male volunteers were included in this study; 36 of them completed the investigation. Blood samples were withdrawn up to 15 h after start of patch application and plasma concentrations of glyceryl trinitrate were quantified by a GC/MS method. For the areas under the curve from time 0 to the last quantifiable sample, AUC(O-Tlast), mean values of 1545 (test patch, n = 35) and 1686 h.pg/ml (reference patch, n = 35) were found. The corresponding peak glyceryl trinitrate plasma levels were 253 and 263 pg/ml, respectively; they were reached after 6.58 h (test patch) and 7.72 h (reference patch). The statistical comparison (ANOVA, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both patches. Typical side-effects known and described under glyceryl trinitrate therapy were also observed in this study.

Administration, Cutaneous↗

PubMed1994

Bioequivalence evaluation of the metabolites 1,2 and 1,3-glyceryl dinitrate of two different glyceryl trinitrate patches after 12-h usage in healthy volunteers.

In the course of this study both the bioavailability and main pharmacokinetic parameters of the glyceryl trinitrate (GTN, CAS 55-63-0) metabolites 1,2 and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) were to be determined following transdermal application of a glyceryl trinitrate test patch (Deponit 5) and an already marketed reference patch. For this purpose, both patches were examined in healthy volunteers according to a randomized two-way cross-over design, blood samples were withdrawn up to 15 h after start of patch application and the plasma concentrations of both metabolites were quantified using a GC/MS method. The investigation showed the following results: Metabolite 1,2-glyceryl dinitrate: For the area under the curve from time 0 to the last quantifiable sample (AUC(0-Tlast) arithmetic mean values of 23.77 h.ng/ml (test patch) and 27.83 h.ng/ml (reference patch) were found. The corresponding peak plasma levels were 2.45 ng/ml and 2.93 ng/ml, respectively; they were reached after 6.4 h (test patch) and 8.31 h (reference patch). Metabolite 1,3-glyceryl dinitrate: The arithmetic mean values for AUC(0-Tlast) were 3.32 h.ng/ml (test patch) and 3.81 h.ng/ml (reference patch). The maximum plasma levels were 0.35 ng/ml and 0.41 ng/ml for the test and reference preparation, reached after 6.4 h and after 7.86 h, respectively. The statistical comparison (ANOVA, confidence intervals) showed bioequivalence between both patches concerning the metabolites investigated. The typical side effects known after nitrate therapy also occurred in the course of this study.

Administration, Cutaneous↗

PubMed1993

Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve.

The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II-III) with elevated PAPd at rest (> or = 15 mmHg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min. The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.

Adult↗

PubMed1993

Bioavailability and pharmacokinetics of a new isosorbide dinitrate spray preparation in healthy volunteers.

In the course of this study the bioavailability and pharmacokinetic profile of a newly developed 2.5 mg (per valve release) oral isosorbide dinitrate (ISDN, CAS 87-33-2) spray preparation (Isoket Spray) were determined and compared with the results for an already marketed reference spray preparation following single application. For this purpose, the test and reference spray were examined in 18 healthy volunteers according to a randomized 2-way cross-over design. Blood samples were collected during 12 h p.a. and plasma concentrations of ISDN and its metabolites isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were quantified by a GC-method. Both sprays showed mean maximum concentrations of ISDN in plasma of nearly 18 ng/ml about 7 min after drug intake with arithmetic mean values for the areas under the curve AUC0-12 of 7.01 (test spray) and 7.30 h.ng/ml (reference spray). For the metabolic products IS-2-MN and IS-5-MN (values for the reference spray in brackets) the corresponding maximum concentrations were 4.15 (4.21) ng/ml and 16.1 (15.9) ng/ml, respectively, and for the areas under the curve AUC0-12 values of 9.75 (9.92) h.ng/ml for IS-2-MN and 104.3 (99.7) h.ng/ml for IS-5-MN in the mean were calculated. Statistical evaluation of all pharmacokinetic parameters revealed bioequivalence between the two preparations. Typical side-effects known and described under isosorbide dinitrate therapy were also observed in this study.

Adolescent↗

PubMed1993

Transdermal nicotine substitution: pharmacokinetics of nicotine and cotinine.

The use of tobacco has resulted in major health related problems worldwide. Nicotine replacement is one of the most promising strategies in smoking cessation. The in vivo delivery rate and the pharmacokinetic properties of a recently developed transdermal nicotine system (TNS) was investigated in three separate studies. Two sizes (16 cm2 and 24 cm2) of the patches were tested. Mean daily nicotine delivery, expressed by a first order kinetic, varied between 0.9 and 1.0 mg/cm2 patch. The different sizes of the patches led to linearly dose-related nicotine plasma Cmax- and AUC-values. The nicotine levels achieved were in the same range with those of other nicotine patches and the chewing gum. As a result of multiple dose kinetic, no significant accumulation of nicotine was observed. Mean elimination half-life of nicotine after removal of the patches (3.5 +/- 1.8 h for the larger patch and 4.5 +/- 1.9 h for the smaller patch) was longer than reported values after i.v. administration, which was reported to vary between 40 and 120 min.

Administration, Cutaneous↗

PubMed1992

Pharmacodynamic and pharmacokinetic evaluation of a new transdermal delivery system with a time-dependent release of glyceryl trinitrate.

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo-controlled study design with an application period of active drug of 4 successive days. The adhesive-type matrix system contains 20-mg GTN and released about 75% in a time-dependent manner. The plasma concentrations of GTN and its metabolites 1-2- and 1-3 glyceryl dinitrate reflected the time-dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b-ratio of the digital pulse (height of the peak of the systolic wave divided by height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.

Administration, Cutaneous↗

PubMed1992

Evaluation of bioavailability and pharmacokinetics of two isosorbide-5-mononitrate preparations in healthy volunteers.

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of two commercial 20-mg isosorbide-5-mononitrate (IS-5-MN) preparations (test and reference preparation) after single oral administration. For this purpose, the test and the reference preparation were examined in 24 healthy male volunteers according to a randomized 2-way cross-over design, blood samples were withdrawn up to 24 hours postadministration, and plasma concentrations of IS-5-MN were quantified by a gas chromatography (GC) method. Both preparations led to peak plasma levels of approximately 360 ng/mL IS-5-MN in the mean 0.76 hour (test) and 0.94 hour (reference preparation) after application; the plasma half-lives were about 5.2 hours, and for the areas under the curve (AUC(0-infinity)), mean values of 2741 (test preparation) and 2742 hour.ng/mL (reference preparation) were found. The statistical comparison (analysis of variance, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both IS-5-MN preparations. The undesired side effects/concomitant symptoms observed are known to occur after IS-5-MN administration.

Administration, Oral↗

PubMed1991

Haemodynamic effects of glyceryl trinitrate following repeated application of a transdermal delivery system with a phasic release profile.

The haemodynamic effects and plasma concentrations of glyceryl trinitrate (GTN) and its dinitrate metabolites were investigated in 8 healthy male volunteers during 5 days of application of a new transdermal delivery system (TDS) with time-dependent release characteristics, which were considered to prevent or to diminish development of nitrate tolerance. On the first and fifth day of administration the following haemodynamic parameters were determined: digital pulse ratio of height of systolic peak to height of dicrotic wave (i.e. a/b-ratio), heart rate and systolic blood pressure under orthostatic conditions. Peak plasma concentrations of GTN were 139 and 155 pg.ml-1 on the first and fifth day of treatment, and the corresponding trough concentrations (i.e. 24 h after administration) were 52.5 and 36.6 pg.ml-1, respectively. Compared to placebo, the area under the effect curve of the a/b-ratio of the digital pulse was increased on the first (25.6%) and fifth day (13%). A significant increase of heart rate and a decrease of systolic blood pressure were seen only on the first day of treatment. The haemodynamic effects of sublingual GTN 0.8 mg were reduced by 69% (a/b-ratio) and 52% (standing heart rate) on the fifth day compared to the pretreatment values. Thus, the phasic release of GTN from the new TDS can be demonstrated by the time course of the plasma concentrations of GTN and its metabolites. Nevertheless, following repeated administration the hemodynamic effects are blunted.

Administration, Cutaneous↗

PubMed1989

Pharmacokinetics of isosorbide dinitrate, isosorbide-2-nitrate and isosorbide-5-nitrate in renal insufficiency after repeated oral dosage.

The pharmacokinetics of isosorbide dinitrate (ISDN) and its two active metabolites isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were studied in 20 patients with normal and impaired renal function after repeated oral doses of standard 20 mg tablets ISDN t.i.d. Blood samples were taken in the steady-state on days 2 and 14, and the plasma concentrations were measured by electron capture capillary gas chromatography. We found a wide variation of pharmacokinetic parameters (AUCss0-8 and t1/2) of ISDN, IS-2-N, and IS-5-N in our patients. No correlation was detected between AUCss0-8 or t1/2 and the degree of renal insufficiency. No drug accumulation was observed after 14 days of administration.

Administration, Oral↗

PubMed1989

Principles of transdermal nitroglycerin administration.

The currently marketed delivery systems for transdermal nitroglycerin (GTN) develop fairly constant GTN plasma concentrations throughout the 24-h application period. This may be associated with tolerance, particularly when higher doses are employed. Because of this problem, a new GTN transdermal delivery system (TDS) has been developed which provides a time-dependent, non-constant drug delivery rate. This system was engineered to provide high GTN plasma concentrations during the first 12h of application which should prevent exercise-induced angina and low nitroglycerin levels during the second 12-h period to prevent tolerance. This GTN TDS with a phasic release profile is described and the in vitro and in vivo release rates and resulting plasma concentrations are contrasted with those of conventional GTN transdermal patches.

Administration, Cutaneous↗

PubMed1989

[Bioavailability of sustained-release and nonsustained-release isosorbide-5-mononitrate].

Bioavailability of Sustained Release and Non Sustained Release Isosorbide-5-Mononitrate. In a randomized, open cross-over study in 18 healthy subjects plasma concentration of isosorbide-5-mononitrate (IS-5-MN) after oral administration was determined over 24 h by gas chromatography. A single dose of three sustained release and two standard preparations was given: (A) a capsule (Elantan), 50 mg; (B) a development tablet, 50 mg and (C) a development capsule, 100 mg; furthermore (D) and (E) non sustained release tablets, 40 and 2 x 20 mg, of two different producers. (D) was considered as reference preparation. Standard preparations (D) and (E) were bioequivalent. But maximum plasma concentrations (cmax) of all sustained release preparations were significantly lower from 13% (C) to 53% (A). Also the moment of maximum plasma concentrations (tmax) occurred significantly later between 2 h 40 min and 3 h 50 min. A significant loss in relative bioavailability was observed for (A) with 82.5% and for (C) with 81.4%. (B) achieved the highest relative bioavailability (93.9%) of the sustained release preparations (n.s.). "Therapeutic concentrations" above 100 ng/ml over 24 h were maintained only by (C). Terminal elimination half-lives were calculated between 5.5 and 6.5 h (mean). Plasma concentration-time curves were simulated in steady state.

Biological Availability↗