The behaviorally active peptide ACTH 4-10: Measurement in plasma and pharmacokinetics in man

Summary A specific radioimmunoassay for the quantitative measurement of ACTH 4-10 and a procedure for its extraction from plasma have been developed.Its pharmacokinetics was studied in eight healthy male volunteers given ACTH 4-10 125 µg/kg body weight as a bolus i.v. injection, by infusion and intranasally. Following the i.v. bolus, plasma levels rapidly declined biexponentially, with half-lives of 0.39±0.05 min for the -phase and 3.84 ± 1.5 min for the -phase (mean±SD). The constant rate i.v. infusion yielded steady-state levels between 0.74 and 5.06 ng/ml plasma. Administered as intranasal spray, absorption of intact ACTH 4-10 was low and variable (maximal bioavailability 7.6%).The results are discussed in relation to the dose-dependent effects of ACTH 4-10 on the auditory evoked potential.     

The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer

Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5-deoxy-5-fluorouridine (5dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5dFUR (2 and 4 g · m^–2) on separate days.Plasma concentrations of 5dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min^–1) but no apparent change in renal clearance (0.32 to 0.29 l · min^–1) or steady-state apparent volume of distribution (19.8 to 20.4 l).The mechanism for dose-dependence of 5dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.     

Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects

Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet.Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t_1/2 of the elimination phase () was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h^–1 and the plasma carnitine clearance was 5.4 vs 6.11 × h^–1 (p<0.025), thus showing dose-related elimination.Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70% and 82% during the first 24 h, respectively.Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8% and 4% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16% and of the 6 h dose 5%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.     

Dosage guidelines for the use of vancomycin based on its pharmacokinetics in infants

Summary The purpose of this study was to characterize the pharmacokinetics of vancomycin and to develop optimal dosage guidelines in infants. Thirteen infants between the ages of 13 to 183 days were enrolled. All had been born prematurely, and average gestational age, postconceptional age, and actual body weight were 29.8 weeks, 38.2 weeks, and 2.1 kg respectively. Multiple blood samples were obtained from each patient after 72 h of therapy. Serum inhibitory and bactericidal titres were determined for peak and trough samples.There were good correlations between total body clearance of vancomycin and both postconceptional age (r=0.86) and actual body weight (r=0.87). This information was used to develop vancomycin dosage guidelines in premature infants. The regression line for vancomycin daily dosage requirements vs postconceptional age may be useful for determining initial dosage recommendations.There were also good correlations between vancomycin serum concentrations and serum inhibitory and cidal titres. Peak and trough concentrations in the therapeutic range (peak, 25–35 µg/ml; trough, 5–10 µg/ml) corresponded to titres of 1:8 and 1:2 to 1:8 respectively.Based on these data we suggest the following dosage guidelines for vancomycin: 10 mg/kg 12 hourly for 30–34 weeks postconceptional age and <1.2 kg actual body weight; 10 mg/kg 8 hourly for 30–42 weeks postconceptional age and >1.2 kg actual body weight; 10 mg/kg 6 hourly for >42 weeks postconceptional age and >2.0 kg actual body weight.Thus, doses which are lower than currently recommended are needed for infants born prematurely. Furthermore, the initial dose of vancomycin can easily be determined using an infant's postconceptional age.SML was a Fellow at Children's Hospital at the time of study and is now at Rutgers University, College of Pharmacy, Piscataway, NJ, USA     

Determination of a buspirone metabolite in plasma samples

A high-performance liquid chromatographic (HPLC) method is described for the assay of the active metabolite [1-(2-pyrimidinyl)piperazinel of buspirone, an anxiolytic agent, in rat plasma.

The method is based on the use of ion-pair HPLC coupled to a liquid—solid extraction scheme. Samples of rat plasma (2 ml) with internal standard (1-phenylpiperazine), adjusted to pH 10.5 with borate buffer, were loaded on to a preactivated C-18 cartridge. The metabolite and the internal standard were eluted with 5 ml of methanol and injected on to a reversed-phase 10-μm Spherisorb ODS-2 column. The column was eluted with a mobile phase of 0.005 M sodium lauryl sulphate in citrate buffer (pH 3.6)-acetonitrile (65:35, v/v) at 2 ml min⁻¹. Detection was carried out at 248 nm. The recovery of the metabolite was 55%. The method was applied to the determination of the metabolite in rat plasma after oral dosing (25 mg kg⁻¹) of the parent compound.     

Pharmacokinetics and tolerance of a new penem antibiotic,FCE 22101, in healthy volunteers after a single intravenous dose

Summary The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg·kg^–1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (C_max) was 15.5 (1.08) µg·ml^–1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [ =44.2 (4.2) min; CL=7.21 (0.47) ml·kg^–1·min^–1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml·kg^–1. The mean residence time relative to the 10 min infusion was 39.4 (1.5)min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.     

Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children

Summary We have studied the mechanisms of the increased dosage requirements of the H₂-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study.Cimetidine (10–15 mg·kg^–1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis.The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml^–1.The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg^–1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg^–1 and 2.21 h respectively.Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min^–1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r ²=0.85).The plasma concentration of cimetidine needed to increase gastric pH to 4.0 was 1.0 µg·ml^–1, which contrasts with the value of >0.5 µg·ml^–1 required for adult burned patients.These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.     

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl);weight was inferior to age and did not statistically improve the model (p>0.005when combined with age. Total Clincreased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Clvalues: for a given age, Clwas 34% higher for blacks than the reference population composed of the remaining patients, and Clfor males was 25% higher than that for females. The volume of distribution (Vdfor the population was estimated to be 0.62 L/kg. The interindividual variability in Cland Vdexpressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 g/ml. The STCs that represented some degree of outpatient dosing were 21 % lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.     

Comparative distribution,pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid,all-trans-4-oxo-retinoic acid,retinyl acetate and 9-cis-retinal in hamsters

Pregnant hamsters were given a single oral dose (35 mol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid; 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t 1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.     

Distribution of thietazole in organs and tissues of rats after single and repeated administration

We studied the kinetics of thietazole distribution in the liver, brain, kidneys, spleen, heart, skeletal muscles, lungs, adipose tissue, and testicles after single and repeated administration of this drug. Single and repeated administration of thietazole was followed by elimination of this drug from the blood into organs and tissues. After repeated administration, thietazole was selectively accumulated in the spleen. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 5, pp. 555–557, May, 2008