bluuebunny/crossref_metadata_2025_split huggingface dataset:
Organ distribution and stability of phosphorothioated oligodeoxyribonucleotides in mice
Authors: Goodarzi Goodarz , Watabe Misako , Watabe Kounosuke 
Published: October 2006

AbstractResults of recent studies in our laboratory have suggested a potential role for antisense oligodeoxyribonucleotides (oligo(dN)s) as therapeutic agents in the treatment of human hepatitis B virus infection. As a first step towards assessing the potential utility of oligo(dN) in therapy, we have examined the organ distribution, stability and toxicity of a phosphorothioated oligo(dN) (S‐oligo) of 20 nucleotides in length which was administered to mice via different routes. Among the various organs analysed, the liver retained the highest amount of S‐oligo (1·3–2 per cent of the total injection) at the peak time (10–30 min) regardless of the route of injection. However, the S‐oligo appeared to be degraded in the liver to about 40 per cent of its original length within 30 min of injection, presumably by the action of 3′ exonucleases. Injection of doses of up to 5 mg kg−1 of S‐oligo had no apparent toxic effects on the mice.
Pharmacodynamics as a tool to assess the bioequivalence of nonystemically available drugs: Size of the sample required
Authors: Souich Patrick Du , Besner Jean‐Guy , Caille Gilles 
Published: October 2006

AbstractBioequivalence studies of drugs which are not systematically available must rely on the measure of the pharmacological response. Detection of a difference between two such preparations is often hampered by the need to include an elevated number of subjects. The number of subjects can be reduced whenever: (a) the characteristics of the subjects are well defined, (b) the selection of the baseline target effect is done rigorously, (c) the target effect can be quantified reliably, (d) the effect is measured when less variability is expected, e.g. at steady state, (e) the effect is measured repeatedly, and (f) when possible, the predicted maximal effect (Emax) and the concentration to elicit 50% of Emax are estimated. A simple equation has been derived to estimate the number of subjects needed in these bioequivalence studies.
Comparison of disposition behavior and de‐coppering effect of triethylenetetramine in animal model for Wilson's disease (long‐evans cinnamon rat) with normal Wistar rat
Authors: Iseki Ken , Kobayashi Michiya , Ohba Ayumi , Miyazaki Katsumi , Li Yu , Togashi Yuji , Takeichi Noritoshi 
Published: October 2006

AbstractThe disposition behaviors and de‐coppering effect of triethylenetetramine dihydrochloride (trientine), a selective chelating agent for copper and an ‘orphan drug’ for Wilson's disease, have been evaluated in an animal model, Long‐Evans Cinnamon (LEC) rats, and normal rats (Wistar). In LEC rats, urinary excretion of trientine was remarkably lower than that of Wistar rats. The absorption rates from the jejunal loop and in vitro metabolism in the liver S9 fraction (supernatant of 9000 × g) were approximately the same for both strains. The decline of urinary excretion of trientine in LEC rats is thought to be due mainly to the lowering of the functional activity of the kidney, because urinary excretion of creatinine and phenolsulfonphthalein were significantly lower in LEC rats than those in Wistar rats. Both acceleration of urinary excretion of copper and reduction of hepatic copper levels were observed with treatment of trientine in LEC rats aged 6 weeks. In LEC rats aged 13 weeks, however, no de‐coppering effect from the liver was observed, though urinary excretion of copper was increased. These results suggest that trientine has a pharmacological effect in disease state, especially in the early stages of hepatitis.
Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man
Authors: Oliary J. , Tod M. , Nicolas P. , Petitjean O. , Caillé G. 
Published: October 2006

AbstractThe pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 × 400 mg doses of Nurofen® were determined in 12 healthy volunteers. Terminal half‐lives were similar for both enantiomers, but plasma levels of S‐ibuprofen were higher than those of R‐ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time‐dependency. A large inter‐individual variability in the ratio of S‐ to R‐ibuprofen average concentrations at steady‐state was observed (mean ±SD 1·89±0·89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.
Extrahepatic production of the lignocaine metabolite monoethylglycinexylidide (MEGX)
Authors: Sallie R. W. , Tredger J. M. , Williams R. 
Published: October 2006

AbstractThe extrahepatic production of monoethylglycinexylidide (MEGX) from lignocaine was measured in a 20‐year‐old female rendered anhepatic while awaiting liver transplantation 4 days after a paracetamol overdose. Following hepatectomy and during continuous arteriovenous dialysis, cardiac stability and control over rising intracranial pressure was restored. Lignocaine (1 mg kg body weight−1 intravenously over 2 min) reached a subtherapeutic peak serum concentration of 0·89 mg 1−1 and was rapidly and exponentially cleared, reaching the lower limit of detection after 5 h (cf. around 2 h in normal subjects). There was significant production of MEGX at extrahepatic sites with serum concentrations rising from undetectable levels to 15 μg 1−1 at 15 min and to a peak of 30 μg 1−1 at 2 h and falling thereafter. MEGX concentrations were similar in arterial, venous, and pulmonary arterial blood, suggesting minimal MEGX production in the heart, lungs or skeletal muscle. Extrahepatic production of MEGX may contribute to total MEGX formation and should be considered when interpreting test results.
Input rate‐dependent stereoselective pharmacokinetics: Enantiomeric oral bioavailability and blood concentration ratios after constant oral input
Authors: Mehvar Reza 
Published: October 2006

AbstractA pharmacokinetic model and relevant equations were used to simulate the blood concentration ratio (Cratio) and oral bioavailability ratio (Fratio) of the two enantiomers of model racemic drugs after different oral input rates. The simulations were carried out for six metabolically eliminated racemic drugs with regard to differences between the two enantiomers in their metabolic maximum velocity (Vmax) and/or Michaelis‐Menten constant (Km). Both Cratio and Fratio values were dependent on the oral input rate of the drugs, with the maximum sensitivity observed for input rates close to the Vmax of the enantiomers. However, at input rates substantially lower or higher than Vmax, the dependence of ratios to input rate was minimal. The profile of dependence of Cratio and Fratio on the input rate differed for the various modeled drugs and, in one case, input rate alteration lead to a reversal in the stereoselectivity of the ratios. Relevance of these findings with regard to alterations in the dose and/or formulation of racemic drugs is discussed.
Clinical pharmacokinetics of procaterol: Dose proportionality after administration of single oral doses
Authors: Eldon Michael A. , Blake Debbie S. , Coon Michael J. , Nordblom Gerald D. , Sedman Allen J. , Colburn Wayne A. 
Published: October 2006

AbstractProcaterol is a potent, orally active β2‐agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effective when administered as single or multiple (Q8H) 50 and 75 μg doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 μg doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for tmax, the apparent elimination rate constant, Cl/F, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose‐normalized AUC, Cmax, and amount excreted unchanged in urine (Ae) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied.
Moxisylyte plasma kinetics in humans after intracavernous administration
Authors: Costa Pierre , Bressolle Françoise , Sarrazin Brigitte , Mosser Jacqueline , Navratil Henri , Galtier Marc 
Published: October 2006

AbstractObtaining and sustaining an erection are common problems for the male spinal cord injury patient. Intracavernous injection of vasoactive substances offers a new treatment option but it must be approached with caution in this population. In this work, the use of an alpha‐adrenergic blocking agent, moxisylyte, after intracavernous administration for complete paraplegic patients with erectile impotence is described. During this study, the pharmacokinetic profile of moxisylyte has been defined. Unchanged moxisylyte is not found in plasma, this drug is immediately metabolized after administration. Three metabolites were found in plasma: desacetylmoxisylyte (DAM), conjugated DAM, and conjugates of desmethylated DAM (MDAM). Maximum plasma levels of 72·3 ng ml−1, 301·4 ng ml−1, and 88·8 ng ml−1 are obtained 0·22 h, 0·9 h, and 2·08 h after drug administration for these three metabolites, respectively. The elimination half‐lives are 0·89 h, 2·16 h, and 5·32 h and the MRT, 1·38 h, 3·23 h, and 8·45 h, respectively. No side‐effects were noted, only one patient presented sleepiness. Successful erections (10 to 25 min) were obtained in all patients and no priapism was noted.
Pharmacokinetics of progesterone in ovariectomized rats after single dose intravenous administration
Authors: Gangrade Nutan K. , Boudinot F. Douglas , Price James C. 
Published: October 2006

AbstractThe pharmacokinetics of progesterone were characterized in ovariectomized female rats. Progesterone was administered intravenously at a dose of 500μg kg−1. Serum progesterone concentrations were determined by radioimmunoassay. Serum concentrations of progesterone were best described by a two‐compartment model with elimination from the central compartment. The distribution and elimination phase half‐lives were 0·13±0·024 (mean±SD) and 1·21±0·21 h, respectively. Elimination of the steroid was rapid with a total clearance of 2·75±0·42 1 h−1 kg−1. Progesterone was widely distributed in the rat with a steady state volume of distribution of 2·36±0·23 1 kg−1, a volume of the central compartment of 0·86±0·24 1 kg−1 and a volume of the peripheral compartment of 1·50±0·19 1 kg−1. The results of this study suggest that the ovariectomized female rat is a suitable animal model for examining the pharmacokinetics of progesterone.
Pharmacokinetics and pharmacodynamics of morphine‐3‐glucuronide in rats and its influence on the antinociceptive effect of morphine
Authors: Ekblom Marianne , Gårdmark Marie , Hammarlund‐Udenaes Margareta 
Published: October 2006

AbstractIn this study the pharmacokinetics and pharmacodynamics of morphine‐3‐glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 μmol kg−1) and as a constant rate infusion (2.9 μmol h−1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 ± 0.6 ml min −1* kg, the volume of distribution at steady state (Vss) 1.68 ± 0.89 1 kg−1, the half‐life of the first phase 13.2 ± 1.8 min and the halflife of the second phase 11.6 ± 7.7 h. After the constant rate infusion, Cl was 10.5 ± 1.7 ml min−1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 μmol kg−1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.
Pharmacokinetics and bioavailabilities of hymecromone in human volunteers
Authors: Garrett Edward R. , Venitz Jürgen , Eberst Kathleen , Cerda James J. 
Published: October 2006

AbstractSpecific and ultrasensitive reverse‐phase HPLC assays of the choleretic and biliary antispasmodic hymecromone (down to 0.05 ng ml−1) and its glucuronide, using fluorimetric detection, and sulfate metabolities using UV detection, were developed. Sodium salt solutions of 400 mg (over 3 min) and 800 mg (over 5 min) were infused i.v. into 6–8 normal human volunteers. The half‐life of the major rate constant averaged 28 ± 2 min (SE). Subsequently, less than 0.8 per cent of the dose was eliminated with terminal halflives of 70–359 min. The apparent volume of distribution of hymecromone, referenced to the total plasma concentration, averaged 20.8 ± 1.41 (Vc, central compartment volume) and 36.4 ± 2.11 (Vss steady state volume). Hymecromone's total body clearance averaged 1413 ± 89 ml min−1. The pharmacokinetics of hymecromone were doseindependent. Only 0.3 ± 0.3 per cent unchanged hymecromone was renally excreted. Mostly dose‐independent glucuronidated drug (93 ± 4 per cent of the dose) was excreted in the urine; a smaller amount was renally excreted as the sulfate (1.4 ± 0.3 per cent of the dose). The oral bioavailability estimated from the relative areas under the hymecromone plasma concentration—time curves following oral and i.v. administration of hymecromone to six volunteer subjects showed no dose‐dependence and was 1.8 ± 0.6 per cent. However, an anomalous c. 200 per cent of the glucuronide produced by i.v. hymecromone was produced from orally administered hymecromone as determined from the ratio of the AUC values of glucuronide obtained after peroral and i.v. administration of the same dose of hymecromone to demonstrate a high first‐pass effect and implicate renal glucuronidation.
Study on pharmacokinetics of a new biliary excreted oral angiotensin converting enzyme inhibitor, temocapril (CS‐622) in humans
Authors: Suzuki H. , Kawaratani T. , Shioya H. , Uji Y. , Saruta T. 
Published: October 2006

AbstractDespite the usefulness of angiotensin converting enzyme (ACE; EC 3.4.15.1) inhibitors for patients with renal insufficiency, some hesitation has been exercised in applying ACE inhibitors to the treatment of such patients because most ACE inhibitors are excreted mainly into the urine. In this context, development of an ACE inhibitor which is excreted into the bile has been sought.The pharmacokinetic properties of the novel ACE inhibitor, temocapril hydrochloride (temocapril HCl; CS‐622), were investigated in six healthy volunteers. This drug is excreted mainly into the bile in animal studies. Temocapril HCl was given in a single dose of 0.5, 1.0, and 2.0 mg, and 36, 44, and 38 per cent of the administered drug was excreted in the feces and 17, 19, and 24 per cent in the urine as the de‐esterified active diacid form (the diacid metabolite) within 48 h, respectively. The plasma ACE activity was markedly inhibited. No abnormal clinical findings suggestive of side‐effects were observed. Thus, from the pharmacokinetic standpoint, temocapril HCl is expected to be a useful drug for patients with renal dysfunction.
Effect of urine pH and ascorbic acid on the rate of conversion of methenamine to formaldehyde
Authors: Strom J. Grady , Jun H. Won 
Published: October 2006

AbstractThe kinetics of conversion of methenamine to the active form formaldehyde were studied in pooled urine samples at 37° in the pH range 4.9–6.5. Using a method for the determination of both formaldehyde and unhydrolyzed methenamine, the rate of formaldehyde formation in urine was found to be apparent first order and was pH dependent. Bactericidal concentrations of formaldehyde (>28 μg ml−1) were achieved in 3 h in urine of pH 6.0 containing methenamine at 750 μg ml−1. There was no difference in the in vitro rate of conversion of methenamine to formaldehyde between the urine collected from normal subjects and the urine from subjects administered ascorbic acid. The rates of degradation of the mandelate and hippurate salts in buffer systems of various pH values did not differ significantly from those of methenamine base in urine adjusted to the same pH. The half‐life of methenamine conversion to formaldehyde increased approximately 20 times from 20 h at pH 5.0 to about 400 h at pH 6.5. The data suggest that unless the urine is maintained below pH 6 only a small fraction of methenamine would be converted daily to formaldehyde and, thus, may explain the need for large doses of this drug in patients.
Blood to plasma ratio of mefloquine: Interpretation and pharmacokinetic implications
Authors: Tajerzadeh H. , Cutler D. J. 
Published: October 2006

AbstractThe blood to plasma ratio of the antimalarial mefloquine has been reported to be close to 1, while other reports indicate extensive accumulation in erythrocytes. This apparent contradiction has been resolved by a quantitative examination of the compensating effects of plasma protein binding of mefloquine which almost exactly matches the extent of mefloquine accumulation in erythrocytes. The observed blood to plasma ratio of about 1 arises as the result of a balance between extensive red cell uptake and extensive plasma protein binding. Some pharmacokinetic implications of the distribution of mefloquine within blood are outlined.
Bioavailability and disposition kinetics of HI‐6 in Beagle dogs
Authors: Baggot J. D. , Buckpitt A. , Johnson D. , Brennan P. , Chung H. 
Published: October 2006

AbstractThe absorption and disposition kinetics of HI‐6 were determined in Beagle dogs given single doses (25 mg kg−1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A twocompartment open model was used to describe the disposition curve following intravenous drug administration while a one‐compartment open model with first‐order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI‐6 was limited (Vss 203 ml kg−1) and the drug was eliminated rapidly after intravenous administration (t1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min−1 × kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24‐h collection period. Following intramuscular drug administration, the absorption half‐life (t1/2(a), 5.3 min), MAT (17.1 min), Cmax (70.37 μg ml−1) and tmax (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t1/2(a) (41.5 min), MAT (81.6 min), Cmax (4.30 μg ml−1) and Tmax (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half‐life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p <0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug.In conclusion, HI‐6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.
Pharmacokinetic study of a tripeptide HIV‐1 protease inhibitor, KNI‐174, in rats after intravenous and intraduodenal administrations
Authors: Kiriyama A. , Mimoto T. , Kiso Y. , Takada K. 
Published: October 2006

AbstractRecently, as a new type of anti‐AIDS drug, an HIV‐1 protease inhibitor, KNI‐174, has been synthesized; it shows a potent and selective HIV‐1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI‐174 in rat plasma and examined the pharmacokinetics of KNI‐174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti‐AIDS drug. This HPLC assay method is specific to KNI‐174 and the standard curve was linear from 0.02 to 30 μg ml−1 plasma. After i.v. administration, 10.0 mg kg−1, KNI‐174 disappeared from the rats' plasma in a three‐exponential decay. The mean terminal elimination half‐life, t1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CLtot, was 9.53 ± 1.08 ml min−1 and the distribution volume at steady state, Vd, ss′ was 7070 ± 960 ml kg−1. In the case of the i.d. administration, 10.0 mg kg−1, the mean peak plasma concentration, Cmax, and the peak time, tmax, were 0.196 ± 0.076 μg ml−1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI‐174 till infinity, BA(0‐infinity), was 5.37 per cent. Because the IC50 of KNI‐174 against HIV‐1 in PHA‐PBM was 138 ng ml−1, the time needed for maintaining the concentrations above IC50 after a single i.d. administration of KNI‐174 is estimated to be 0.350 ± 0.184 h.
Effect of pirenzepine on the N‐demethylation of D(−)ephedrine and ethylmorphine by rabbit liver microsomes
Authors: El‐Obeid H. A. , Al‐Rashood K. A. , Al‐Khamees H. A. , Al‐Khamis K. I. , Mian M. S. 
Published: October 2006

AbstractThe possible interaction of pirenzepine with the mixed‐function oxidases obtained from phenobarbital‐pretreated rabbit microsomes was examined in vitro. Under experimental conditions that did not lead to its own N‐demethylation, the drug inhibited the microsomal oxidase systems responsible for the N‐demethylation of D(‐)ephedrine and ethylmorphine. Kinetic studies showed that pirenzepine inhibited the metabolism of both drugs in a competitive manner. The results indicated that the observed pirenzepine stability to the hepatic N‐demethylating system is not a result of low affinity of the drug to the system.
Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: Analysis by multiple indicator dilution method
Authors: Muranushi Noriyuki , Miyauchi Seiji , Suzuki Hiroshi , Sugiyama Yuichi , Hanano Manabu , Kinoshita Haruki , Oguma Takayoshi , Yamada Hideo 
Published: October 2006

AbstractRilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1(Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution method. The hepatic availabilities (F) of DG and M1, assessed from the recovery into the hepatic vein, were 0.16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first‐pass elimination of M1 was greater than that of DG. The kinetic analysis based on the distributed model showed that the influx (k′1) and efflux (k′2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k′3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k′2 for each ligand were much smaller than the respective k′3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.