Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers.

Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng x mL(-1). The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.     

Single and multiple dose pharmacokinetics of rifapentine in man: part II.

OBJECTIVE: To characterize the pharmacokinetics of rifapentine following single, multiple, and intermittent doses. DESIGN: Twenty-three healthy male volunteers were randomized in a two-period, incomplete block, crossover design to receive two of four possible treatments: single daily oral rifapentine doses of 150, 300, or 600 mg given on day 1 and again on days 4-10, or a single oral 600 mg dose given on days 1, 4, 7, and 10. RESULTS: Maximum rifapentine plasma concentrations were observed in 4-5 hours. Mean rifapentine t(1/2) ranged from 13.2-14.1 hours and was similar across the 150-600 mg dose range. The changes in rifapentine Cmax (R = 0.86) and AUC(0-->infinity) (R + 0.90) were dose linear. The active 25-desacetyl metabolite appeared slowly in plasma, with mean Tmax of 14.4-17.8 hours. Mean t(1/2) for 25-desacetyl-rifapentine ranged from 13.3-24.3 hours. Disproportionate, dose-dependent increases in rifapentine and 25-desacetyl-rifapentine AUC were observed as single doses of rifapentine increased from 150 to 600 mg. At steady state, however, the magnitude of dose dependency was much less. CONCLUSION: Maximum plasma rifapentine concentrations were well above minimum inhibitory concentrations for Mycobacterium tuberculosis and M. avium following single 600 mg doses. In addition, the extended t(1/2) of rifapentine and its active metabolite support clinical investigation of once or twice-weekly rifapentine dosage regimens of rifapentine for the management of tuberculosis.     

Optimal timing of repeated rh-erythropoietin administration improves its effectiveness in stimulating erythropoiesis in healthy volunteers

We studied the effect of recombinant human erythropoietin (rhEPO) on erythropoiesis when given at different time intervals to healthy adults. 15 volunteers were randomly selected to receive rhEPO (2×300 U/kg) and parenteral iron (2×200mg) either within a 24 h or 72 h interval. Controls received parenteral iron only. Maximum EPO levels were found 24 h after the first intravenous injection (day 1) with a mean value of 364 and 390 U/l for the rhEPO-treated groups. When second rhEPO administration was after 72 h (group III), volunteers showed significantly higher absolute reticulocyte counts and a higher percentage of young RNA-rich reticulocytes (HFR ratio) over several days compared to those who received rhEPO within a 24 h interval (group II). Both rhEPO-treated groups showed an increase in the mean reticulocyte cell volume. Reticulocyte haemoglobin concentration was inversely correlated with the increasing cell size with a nadir on day 8. Reticulocyte haemoglobin content showed a significant decrease in group II after day 5. Serum ferritin levels showed an inverse pattern to the rate of erythropoiesis. After an initial rise, the serum ferritin decrease was most pronounced in group III. Contrary to previous reports with oral iron supplementation, functional iron deficiency was not seen during rhEPO stimulation, due to parenteral iron administration. Our data suggest that the time interval between repeated administrations of rhEPO has an important influence on its pharmacodynamics. rhEPO given within an interval of 72 h was more effective in stimulating erythropoiesis than administration within a 24 h interval for the same total dose.     

Dose related pharmacokinetics of ofloxacin in healthy volunteers.

OBJECTIVE: To evaluate the pharmacokinetic profile of ofloxacin in healthy volunteers after single oral doses of 600 and 800 mg. DESIGN: Seven healthy volunteers were administered 600 and 800 mg of ofloxacin on two occasions with an interval of one week. Paired samples of blood and saliva were collected after 1, 2, 3, 6, 9, 12, 24, 32 and 48 hours post-dose. Urine samples were collected over a period of 0-6, 6-12 and 12-24 hours. Concentrations of ofloxacin in plasma, saliva and urine were assayed by high performance liquid chromatography. RESULTS: Increases of 22% in peak plasma concentration (Cmax) and 40% in area under the concentration-time curve (AUC0-24) were observed with the 800 mg dose. The other parameters, namely time to attain Cmax, half-life, the apparent volume of distribution, plasma and renal clearance and percentage of dose excreted in urine over 24 hours were independent of doses. The mean ratios of the concentration in saliva to the concentration in plasma ranged from 0.4-0.6, and the correlation coefficient was 0.94. CONCLUSIONS: Dose proportionality was observed in Cmax and AUC0-24 when 600 and 800 mg doses of ofloxacin were given. Ofloxacin determined in saliva seems to be suitable for therapeutic drug monitoring.     

中国健康受试者多剂口服吉米沙星的药代动力学及药效学研究

目的 研究中国健康受试者对吉米沙星的临床药代动力学(PK)和药效学(PD),为优化临床给药方案提供依据.方法 随机、双盲临床试验中,招募20名健康受试者按1∶1比例分为给药组或对照组,分别予以多剂口服320 mg吉米沙星或安慰剂.高效液相色谱荧光法测定受试者血浆和尿液的药物浓度.采用微量稀释法测定吉米沙星对190株社区获得性肺炎常见临床分离菌株的最低抑菌浓度(MIC).以给药后24 h血浆药物浓度时间曲线下面积(AUC0～24h)与MIC的比值(fAUC0～24 h/MIC)和药物峰浓度(Cmax)与MIC的比值(fCmax/MIC)为指标(靶值为25和5),评价吉米沙星的PK和PD特性,并采用蒙特卡洛模拟评价吉米沙星320 mg 1次/d在稳态血药浓度下对上述细菌的累积反应百分比(CFR)及不同MIC水平下的PD达标概率.采用F检验对各组数据作方差齐性检验,采用t检验分析各组间数据.结果 健康受试者多剂口服吉米沙星320 mg 1次/d连续7d给药后的首剂和末剂Cmax分别为(1.55±0.32)和(1.57±0.31) μg/mL,AUC0～24h分别为(7.91±1.52)和(8.91±1.15)h·μg·mL-1,积蓄因子为1.13±0.05.吉米沙星在受试者体内的PK符合二房室模型,分布相和消除相半衰期分别为(0.64±0.17)和(7.10±2.10)h.首剂和末剂给药后24 h平均累积尿排出率分别达34.83％和38.95％.PD研究显示,吉米沙星对肺炎链球菌和卡他莫拉菌的MIC90分别为0.25和0.125 mg/L,对流感嗜血杆菌的MIC90为2 mg/L,而肺炎克雷伯菌和甲氧西林耐药金黄色葡萄球菌对吉米沙星大部分呈现耐药( MIC90＞32 mg/L).当吉米沙星对细菌的MIC值≤0.06mg/L时,吉米沙星320mg 1次/d连续7d给药方案达到fAUC0～24h/MIC和fCmax/MIC的药效学达标概率值均接近100％.结论 中国健康受试者单剂口服吉米沙星320 mg后吸收迅速,多剂给药后第3天达到稳态血药浓度,连续7d给药后有轻度蓄积.PK/PD分析显示,对该药敏感的社区获得性肺炎和慢性阻塞性肺病急性加重者预期可获得良好的临床和细菌学疗效.     

Non-linear pharmacokinetics of rifampicin in healthy Asian Indian volunteers.

OBJECTIVE: To characterise the pharmacokinetics of rifampicin (RMP) in healthy Asian Indian volunteers after oral administration of commercially marketed reference formulations. DESIGN: Two separate studies were conducted. In Study 1, 12 volunteers were administered a single 450 mg sugar-coated tablet, and in Study 2, 11 volunteers were administered a 30 ml suspension (100 mg/5 ml) equivalent to a 600 mg dose of RMP. Blood samples were collected at 0 hours and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post dose, and plasma concentrations were assayed by high performance liquid chromatography. RESULTS: Non-compartmental analysis indicated that the mean (coefficient of variation [%CV]) values for the tablet for Cmax, Tmax and AUC(0-infinity) were 8.59 (53.66) microg/ml, 1.58 h and 49.54 (61.79) microg x h/ml, respectively. The corresponding mean (%CV) values for the suspension were 14.76 (24.14) microg/ml, 1.45 h and 119.12 (28.24) microg x h/ml. Two-compartment analysis indicated that the mean (%CV) values for Cl/F, beta and t(1/2beta) were respectively 197.51 (46.58) (ml/h)/kg, 0.2153 (32.01) h(-1) and 3.57 (34.85) h, at the 450 mg dose (tablet), and were significantly different from the respective 94.76 (33.96) (ml/h)/kg, 0.1210 (33.66) h(-1) and 5.44 (16.69) h at the 600 mg dose (suspension) (P < 0.05). In addition, there was a significant linear correlation (r = 0.60, P < 0.005, n = 21) between Cmax and the elimination half-life, indicating a concentration-dependent increase in half-life. CONCLUSION: Rifampicin obeys two-compartment kinetics with zero order absorption, and exhibits non-linear saturable elimination kinetics as well as large inter-individual variability.     

Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells

We performed a detailed kinetic study on the in vivo effect of a single subcutaneous dose of granulocyte colony-stimulating factor (G-CSF; 300 micrograms) in four healthy individuals on the expression and function of neutrophil Fc gamma receptors (Fc gamma R). G-CSF did not induce Fc gamma RI (CD64) on circulating neutrophils. However, neutrophils newly formed in response to G-CSF were Fc gamma RI positive and were able to perform antibody-dependent cellular cytotoxicity in an Fc gamma RI- dependent way. Fc gamma RII (CD32) expression was not changed significantly. Fc gamma RIII (CD16, phosphatidylinositol-linked) expression, slightly increased immediately (30 minutes) postinjection, was found to be strongly decreased on the newly formed population. For comparison, we studied the expression of the PI-linked proteins leukocyte alkaline phosphatase (LAP) and CD14. Intracellular levels of LAP mirrored the biphasic expression pattern as membrane-bound Fc gamma RIII. In contrast, CD14 expression on neutrophils was initially constant, followed by high levels on the newly formed neutrophils. Soluble CD14 levels were found to be elevated transiently, whereas peak levels of soluble Fc gamma III were observed as late as 6 days postinjection. In conclusion, we have shown that G-CSF results in an immunophenotypically and functionally altered neutrophil population for an important part as a result of its effect on myeloid precursor cells.     

Differences in pharmacokinetics and pharmacodynamics of insulin lispro and aspart in healthy volunteers.

Pharmacokinetic and pharmacodynamic profiles of the rapid-acting insulin analogues lispro and aspart were compared in a randomized, double-blind crossover study of 20 fasting healthy men following a single subcutaneous injection. Either insulin lispro or aspart, 0.05 U/kg-body-weight, was injected subcutaneously and followed by determination of 5-h profiles of plasma glucose, serum C-peptide and insulin concentrations. Lowest glucose concentrations were observed after 50 min in the aspart group (3.2 +/- 0.1 mmol/l versus lispro 3.5 +/- 0.1 mmol/l; p = 0.026) and after 60 min in the lispro group (3.4 +/- 0.1 mmol/l). For blood glucose t min was 59.3 +/- 3.4 min in the aspart and 63.5 +/- 5.3 min in the lispro group (ns). After 40 min a lower C-peptide was determined for aspart (225 +/- 21 pmol/l versus lispro 309 +/- 33 pmol/l; p = 0.031), whereas minimal C-peptide concentrations were reached in both groups after 105 min (lispro 117 +/- 21 pmol/l versus aspart 105 +/- 18 pmol/l). The maximal concentration of insulin was detected in both groups after 40 min (lispro 20.8 +/- 1.1 mU/l versus aspart 24.6 +/- 1.3 mU/l; p = 0.032). For insulin t max was 33.0 +/- 2.6 min in the aspart versus 33.3 +/- 2.6 min in the lispro group (ns). The present results indicate a more rapid absorption of insulin aspart in comparison to insulin lispro. Higher insulin concentrations after subcutaneus injection may be advantageous in meal-related treatment of diabetes.     

法莫替丁分散片的人体药代动力学及生物等效性评价

目的研究法莫替丁分散片在健康志愿者体内的药代动力学,评价分散片与普通片剂的生物等效性.方法采用随机交叉自身对照设计,10名受试者单剂量口服法莫替丁分散片或法莫替丁普通片40 mg后,采用HPLC法测定血药浓度,评价2种制剂的生物等效性.结果法莫替丁的体内过程符合血管一室开放模型.法莫替丁分散片与普通片剂的Tmax分别为(2.25±0.42)h和(2.40±0.57)h;Cmax分别为(163.29±37.93)μg/L和(162.46±17.91)μg/L; T1/2K分别为(2.39±0.31)h和(2.50±0.44)h;AUC0-t分别为(705.97±202.27)μg*h*L-1和(741.44±168.89)μg*h*L-1,二者间差异无显著意义(P>0.05).结论 2种制剂具有生物等效性,分散片相对生物利用度为94%.     

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.

Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.     

Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.

The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by high-performance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean +/- standard deviation (SD) maximum concentration (Cmax) of AS was 296+/-110 nmol/L, the time to peak blood level (tmax was 0.71+/-0.66 hr, the half-life (t1/2,z) was 0.41+/-0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC](0-12)) was 253+/-185 nmol hr/L. Measured by HPLC, the Cmax and AUC(0-12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948+/-772 and 1,192+/-315 nmol/L; 4,024+/-1,585 and 1,763+/-607 nmol hr/L, respectively; P < or = 0.05). These differences were even greater when measured by BA. The Cmax for patients with malaria was 2,894+/-2,497 and 795+/-455 nmol/L for volunteers, and AUC(0-12) was 5,970+/-3,625 and 1,307+/-391 nmol hr/L, respectively (P < or = 0.05). In contrast, DHA parameter estimates for t1/2,z and tmax were similar between patients and healthy volunteers, with values of 0.80+/-0.30 versus 0.87+/-0.06 hr and 1.50+/-0.55 versus 1.13+/-0.52 hr, respectively (P > 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.     

Sitagliptin: Anti-platelet effect in diabetes and healthy volunteers

Sitagliptin, a selective dipeptidyl peptidase-4 inhibitor drug is used to treat type-2 diabetes (T2DM). We investigated the anti-platelet activity of sitagliptin in patients with T2DM and in in vitro samples obtained from healthy humans. Patients with T2DM (27 male + 23 female) were selected and followed up before (control) and after treatment with sitagliptin for up to 3 months. Platelets were isolated from the blood of sitagliptin treated patients and controls. Patients with T2DM treated with sitagliptin for 1and 3 months, showed 10?±?2% and 30?±?5% inhibition of platelet aggregation, respectively. For the in vitro study, platelets from 10 normal humans (n?=?10) were isolated. Platelet aggregation, intracellular free calcium and tyrosine phosphorylation of multiple proteins were measured by aggregometer, spectrofluorometer and western blotting, respectively. Platelets pre-treated with 5 and 10?µg/ml of sitagliptin, showed 25?±?4% and 40?±?6% inhibition of thrombin-induced platelet aggregation, respectively. Sitagliptin decreased intracellular free calcium (2.5-fold) and tyrosine phosphorylation of multiple proteins in thrombin-induced platelet activation. Sitagliptin inhibited platelet aggregation in T2DM as well as in healthy humans. Sitagliptin has significant concentration-dependent anti-platelet activity. This activity was due to its inhibitory effect on intracellular free calcium and tyrosine phosphorylation.     

The pharmacokinetics of oral dihydroartemisinin and artesunate in healthy Thai volunteers

The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin (Twisinin, T-2 Program, Thailand) and 4 mg/kg body weight oral artesunate (AS; Guilin Pharmaceutical Works, Guangxi, China) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.h/ml, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) l/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) ml/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/ml was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.h/ml, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA.     

The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers

The combination piperaquine and dihydroartemisinin is emerging as first line treatment of uncomplicated falciparum malaria in Southeast Asia. The aim of this study was to determine the influence of a standard Vietnamese meal on the single-dose pharmacokinetics of piperaquine when administered in combination with dihydroartemisinin, and to gain extended data on the terminal half-life of piperaquine in healthy Vietnamese volunteers. Subjects were randomly assigned to take a single oral dose of piperaquine phosphate (640 mg)+dihydroartemisinin (80 mg) together with a standardized Vietnamese meal (n=16) or to remain fasting for 4h following drug intake (n=16). Frequent blood sampling was conducted during 36 h, followed by weekly samples for 7 weeks. The pharmacokinetic parameters of piperaquine were determined by noncompartmental analysis. The median (80% central range) AUC(0-last) was 11.5 (6.9-17.3)h mg/L in fed and 13.9 (2.8-19.3)h mg/L in fasting subjects, indicating a considerable variability in exposure in both groups. The estimated overall oral clearance was 0.27 (0.12-1.49)L/(h kg), the volume of distribution during the terminal elimination phase was 230 (102-419)L/kg and estimated terminal half-life was 18 (5-93) days. This study did not demonstrate a significant impact of a standardized Vietnamese meal on the oral absorption of piperaquine.     

The effect of oral administration of L-arginine on anal resting pressure and anodermal blood flow in healthy volunteers

BACKGROUND: Topical application of L-arginine, the precursor of nitric oxide, reduces anal resting pressure without significant side effects and may therefore be of benefit in the treatment of anal fissure. This in vivo study investigated the effect of orally administered L-arginine on anal resting pressure and anodermal blood flow in healthy volunteers. METHODS: Eight healthy volunteers took 3 sachets of Arginaid (Novartis Consumer Health, Breda, The Netherlands) containing 15 g L-arginine on a daily basis, for 7 days. At the start of the experiment (day 0) and on days 3 and 7, plasma levels of L-arginine, anal resting pressures and anodermal blood flow were determined. RESULTS: Arginine plasma levels increased from 107.0+/-8.6 micromol/l (day 0) to 283.7+/-44.0 micromol/l on day 3 (p< 0.01) and remained elevated at day 7 (157.3+/-19.6 micromol/l, p<0.05). Anodermal blood flow and anal resting pressures were similar on days 0, 3 and 7. CONCLUSIONS: Oral administration of 15 g arginine in healthy volunteers on a daily basis increased arginine plasma levels but had no influence on anodermal blood flow and anal resting pressure.     

Pharmacokinetics of 1-deamino-8-d-arginine vasopressin after various routes of administration in healthy volunteers

OBJECTIVE We investigated the pharmacokinetics and biological effects of 1-deamino-8-d -arginine vasopressin (dDAVP) in healthy adults after intravenous, subcutaneous, intranasal, peroral, sublingual and intrarectal administration. DESIGN Eight normal volunteers were studied over an 8-hour period after each drug administration, separated by at least one week. For intravenous and subcutaneous administration, the subjects received 2 μg of dDAVP. The intranasal and sublingual doses were 20 μg and the rectal dose was 50 μ. Oral administration of dDAVP was effected with a 200-μg tablet. MEASUREMENTS Plasma and urinary levels of dDAVP were measured using a specific and sensitive radioimmunoassay. RESULTS A significant increase of urine osmolality was observed after all routes of administration, except the sublingual and intrarectal for up to 8 hours after administration. After intravenous administration, the half-life of elimination (t) of dDVAP was 78 ± 10 minutes. An extensive adsorption of dDAVP to the plastic syringe was found with intravenous but not with subcutaneous administration. Using the area under the curve of dDAVP from the subcutaneous administration as a reference, bioavailability was found to be 3.4% after intranasal administration and 0.1% after oral administration. After sublingual and intrarectal routes of administration no detectable dDAVP was found in the blood; however, low amounts were found in the total 24-hour urine. CONCLUSION The bioavailability of dDAVP seems lower than previously reported after intranasal and oral administration.