Plasma and salivary pharmacokinetics of caffeine in man

Summary Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163±0.081 h^–1 for 50 mg and 0.098±0.027 h^–1 for 750 mg. The total body clearance was unaffected by dose and was 0.98±0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74±0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.     

Metabolism of phenazone in man after hydrocortisone administration

Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.     

Pharmacokinetics of magnolin in rats

This study was first conducted to characterize the intravenous and oral pharmacokinetics of magnolin, a major pharmacologically active ingredient of Magnolia fargesii, at various doses in rats. Magnolin was administered to rats by intravenous injection (0.5, 1 and 2 mg/kg doses) and oral administration (1, 2 and 4 mg/kg doses), and serial plasma and urine samples were harvested. Magnolin concentrations were determined by a validated LC/MS/MS assay. After both intravenous and oral administration, the AUCs were linearly increased as the dose increased. Other pharmacokinetic parameters of magnolin (except the V _ss after the intravenous administration) were also independent of the doses. The extent of absolute oral bioavailability ranged from 54.3–76.4% for the oral doses examined. Magnolin was considerably bound to rat plasma proteins and the binding value was constant (71.3–80.5%) over a concentration ranging from 500 to 10000 ng/mL. The pharmacokinetic parameters of magnolin were doseindependent after both intravenous and oral administration. When given orally, magnolin was rapidly absorbed.     

Venous Irritation,Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion

Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [¹⁴C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V_ss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.     

Pharmacokinetics and Safety of an Anti-Vascular Endothelial Growth Factor Aptamer (NX1838) Following Injection into the Vitreous Humor of Rhesus Monkeys

Purpose. The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys. Methods. Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye. Results. Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident. Conclusions. The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.     

Pharmacokinetics of CM 57755, a new histamine H2-receptor antagonist, after single oral doses in man

The plasma pharmacokinetics and urinary excretion of CM 57755, an H2-receptor antagonist, were studied after administration of single oral doses in a range between a 100 and 700 mg in human volunteers. Pharmacokinetic parameters were calculated model-independent. Absorption of CM 57755 was bimodal and the maximum plasma concentration was reached between 2 and 4 h after dosing. The drug was widely distributed with an apparent volume of distribution between 140 and 200 l. The plasma clearance was between 56 and 69 L/h. The plasma concentrations declined following a monoexponential function with an elimination half-life of 2 h. No modification in the plasma clearance or other pharmacokinetic parameters with these doses was observed. Therefore, a linear pharmacokinetic profile of CM 57755 was proposed. About 40% of the parent drug was unchanged in urine excreted over the 24 h. The drug was compared with cimetidine and ranitidine, the three compounds seemed to exhibit a consistent pharmacokinetic profile.     

Inter-relationships between the absorptions of hydrocortisone,sodium, water and actively transported organic solutes in the human jejunum

Summary The effect of intraluminal hydrocortisone (100 mg/l) on sodium and water transport in the small intestine was investigated by jejunal perfusion (flow rate 15 ml/min) of healthy subjects with normal saline and saline containing 56 mmol/l galactose or alanine. Minimal absorption of sodium and water occurred with normal saline and did not change significantly in the presence of hydrocortisone. Galactose and alanine enhanced sodium and water absorption and further significant increases occurred in the presence of hydrocortisone. Glucocorticoidinduced increases in absorption were detected within 20–30 min, while plasma cortisol concentrations were in the normal range. 43% of the perfused dose of hydrocortisone was absorbed with normal saline (p<0.01). There was a significant positive correlation (p<0.0025) between hydrocortisone and water absorption. Thus, in the presence of actively absorbed organic solutes, hydrocortisone rapidly increased sodium absorption and the concurrent increase in water absorption appears to have facilitated passive absorption of hydrocortisone.     

Single-dose pharmacokinetics and dose proportionality of oral cibenzoline

The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration-time curve increased in proportion to the dose. The mean elimination half-life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose-proportional and linear pharmacokinetics.     

No influence of single intravenous doses of omeprazole on theophylline elimination kinetics.

The influence of single intravenous doses of omeprazole on the pharmacokinetics of intravenously administered theophylline was studied in eight healthy male volunteers. In a partially randomized three-period crossover design, an IV infusion of theophylline (400 mg over 30 min) was combined with IV omeprazole (either 40 mg over 2.5 min or 80 mg over 5 min) or with IV placebo (over 2.5 min). Theophylline and omeprazole plasma concentrations were measured over 24 hours after the start of the infusions and pharmacokinetic parameters were calculated. The theophylline plasma concentration-time profiles after omeprazole coadministration were virtually identical to the corresponding profile after placebo administration. For each of the pharmacokinetic parameters of theophylline, the 90% confidence intervals of the omeprazole coadministrations were within the 80 to 120% bioequivalence range with respect to the placebo coadministration. Omeprazole plasma concentrations indicated a biexponential decline in most subjects, with a more rapid elimination after the 40-mg than after the 80-mg dose (P less than .01). Doubling the dose caused an almost three-fold increase of AUC resulting in a difference in clearance (P less than .02), whereas the volume of distribution was similar. The results of this study indicate that the metabolism of theophylline is not affected by single intravenous doses of omeprazole. The nonlinear pharmacokinetics of omeprazole are ascribed to saturation of its main metabolizing enzyme, S-mephenytoin hydroxylase.     

Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPCL and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.Supported in part by grant GM-24211 from the National Institutes of General Medical Sciences, NIH.     

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

Summary Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method.Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours.We found a linear relationship (r=0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.     

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; elimination half-life 25 +/- 7h; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/h. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg nocte.     

Pharmacokinetics and oral bioavailability of hydrocortisone

The pharmacokinetics of 20 mg hydrocortisone were studied after IV and oral administration. Endogenous hydrocortisone was suppressed by dexamethasone administration. Hydrocortisone concentrations were measured in plasma and saliva. After IV administration, hydrocortisone was eliminated with a total body clearance of 18 L/hr and a half-life of 1.7 hr. The volume of distribution was 34 L. Oral bioavailability averaged 96%. Absorption was rapid, achieving maximum hydrocortisone levels of 300 ng/mL after 1 hour. Saliva levels were not proportional to plasma levels, but could be shown to reflect free, non-protein bound hydrocortisone concentrations in plasma.     

Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs

The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P > 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.     

Pharmacokinetics of butofilolol (CAFIDE) after repeated oral administration in man

The pharmacokinetics of butofilolol, a new beta-blocking drug, was studied in 6 healthy subjects. Plasma concentrations and urinary excretion of the unchanged drug were determined after a single 100-mg oral administration, and also during chronic treatment (100 mg/day for a week) and after the last dose. Maximum plasma concentrations were observed 2 to 3 h after drug administration and varied between the subjects (120 to 430 ng/ml). The apparent volumes of distribution were large, ranging between 200 I and 500 I, and the apparent clearances of elimination appeared to be intermediate between 40 and 70 l/h. Drug elimination in the urine (about 4% of administered dose) occurred by filtration, tubular secretion and pH-sensitive reabsorption following a non-linear process. However, pharmacokinetic parameters remained constant during chronic treatment, since urinary elimination of the parent drug was too low to influence its pharmacokinetic profile. In addition, a high correlation was found between plasma levels of butofilolol and the effect of the drug on resting heart rate, while a slight effect on diastolic blood pressure could be discerned.     

Comparative pharmacokinetics of antipyrine (phenazone) in the baboon,cynomolgus monkey and rhesus monkey

The pharmacokinetics of antipyrine (phenazone) in 3 species of non-human primate have been evaluated following its intravenous administration at a dose level of 92 mg/kg.Mean peak plasma concentrations of antipyrine of 132, 137 and 155 μg/ ml in the rhesus monkey, the cynomolgus monkey and the baboon respectively were not observed until 5 min after intravenous injection. Thereafter, concentrations declined with an apparent half-life of elimination of 1.5–2 h. The time-course of plasma antipyrine concentrations was adequately described by a one-compartment open model and no notable differences in pharmacokinetic parameters utilising a 2-compartment open model were observed.Antipyrine was mainly distributed in total body water. The mean volume of distribution was equivalent to 88, 73 and 66% of body weight in the rhesus monkey, the cynomolgus monkey and the baboon, respectively.An analysis of variance of volumes of distribution, apparent half-lives of elimination and systemic clearances showed that there was a statistically significant species-related difference in systemic clearance (P < 0.05) and volumes of distribution (P < 0.01) which were lower in the cynomolgus monkey than in the other 2 species.The pharmacokinetics of antipyrine in the non-human primate are more similar to those of other laboratory animal species than to those of humans.     

Pharmacokinetics of prednisolone after high doses of prednisolone hemisuccinate

Prednisolone in the form of its hemisuccinate was given intravenously in two different doses (1200 mg and 75 mg). Plasma levels of the ester and prednisolone were measured and pharmacokinetic parameters were calculated. The results indicate a dose-dependency in the pharmacokinetics of both hemisuccinate and the free alcohol. For the high dose 8 per cent of the administered ester was found unchanged in the urine indicating incomplete conversion of the pro-drug. Comparison with previous studies leads to the conclusion that prednisolone shows doubled non-linear pharmacokinetics with higher total body clearance in the medium dose range than in the low and high dose range. Volume of distribution changes accordingly, but overall elimination rate remains remarkably constant. Saliva levels of prednisolone were low and agree reasonably well with calculated plasma concentrations of free, non-protein-bound prednisolone. No prednisolone hemisuccinate was found in saliva.     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

单次静滴人参皂苷-Rd注射液在中国健康志愿者的药代动力学及耐受性

目的 研究中国健康志愿者单次静滴人参皂苷-Rd(防治脑缺血中药)注射液的药代动力学及耐受性.方法 选12名健康志愿者,按双拉丁方设计分组,每位受试者于3个周期内交叉静脉滴注人参皂苷-Rd注射液10、40、75 mg 3个剂量;用LC/MS/MS法测定血浆人参皂苷-Rd浓度,用DAS软件计算药代动力学参数;试验过程中密切观察药物不良反应.结果 3个剂量(10、40、75 mg)的主要药代动力学参数:Cmax分别为(2.84±0.47)、(10.48±1.74)、(19.34±2.62)mg·L-1,t1/2分别为(19.29±3.44)、(18.41±2.92)、(17.67±2.01)h,AUC0-t分别为(27.26±8.12)、(112.62±24.08)、(208.36±51.36)mg·L-1·h-1,Cmax、AUC0-t与剂量的线性关系良好,随给药剂量的增加基本成比例增加.试验过程中未出现严重不良事件.结论 该药在中国健康受试者的体内过程符合线性药代动力学特征,剂量在10～75 mg内较安全.     

Population Pharmacokinetic Meta‐Analysis of Vortioxetine in Healthy Individuals

The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5–60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two‐compartment model with first‐order absorption, lag‐time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97?10³ L for the central volume of distribution. The average elimination half‐life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate–parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population.