bluuebunny/crossref_metadata_2025 huggingface dataset:
Linear pharmacokinetics of haloperidol in the rat
Authors: Cheng Y. F. , Paalzow L. K.
Published: October 2006

Pharmacokinetics of haloperidol in the rat following intravenous bolus doses of 0·5, 1·0, and 2·5 mg kg−1, respectively, were investigated. It was found that haloperidol was a high extraction ratio drug with a total blood clearance averaging 83 ml min−1 kg−1. The volumes of distribution were large with a mean of 5·5 1 kg−1 (Vc), 11·11 kg−1 (Vβ), and 9·61 kg−1 (Vss), respectively. The terminal half‐life was 1·5h. The disposition kinetics of haloperidol was found to be linear over the dose range studied. After constant intravenous infusions of haloperidol by different infusion rates during 12h, steady‐state levels were reached in the blood. The measured steady‐state blood concentrations were consistent with those predicted by a biexponential infusion model based on the parameters obtained from the intravenous bolus study. The total blood clearance at steady‐state was concentration‐independent within the investigated range of 5 to 20 ng ml−1.
Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats: I
Authors: Harashima Hideyoshi , Ohshima Shunji , Midori Yukari , Yachi Kiyoto , Kikuchi Hiroshi , Kiwada Hiroshi
Published: October 2006

The purpose of this study was to perform a kinetic analysis of the tissue distribution of doxorubicin (DXR) and liposomes separately after intravenous administration of DXR entrapped in liposomes in rats. Liposomes were double labeled with 14C‐DXR (L‐DXR) and 3H‐inulin (L‐INU). Blood and tissues were sampled at specified times until 120 min. Blood clearance of L‐DXR was similar to that of L‐INU. Distribution of both L‐DXR and L‐INU into the liver was parallel and extensive, while in the heart, the pattern of distribution differed between L‐DXR and L‐INU after peak concentration. Time courses of tissue concentration were explained well by dividing tissue into a shallow compartment with efflux and a deep compartment without efflux. In the liver, pharmacokinetic parameters of L‐DXR and L‐INU were similar, and the two kinetically different compartments may correspond to different uptake processes in hepatic endocytosis. In the heart, the shallow compartment was considered to correspond to the cardiac vascular space, and the intercompartmental rate constant (k3) for L‐DXR was much larger than that for L‐INU. The estimated half‐life for this process was 20 min. The half‐life for the degradation of liposomes in blood circulation was also estimated at 20 min from data on the urinary excretion of released 3H‐inulin. These results suggest that the release of DXR from liposomes may be the rate‐limiting process in the tissue distribution of DXR to the heart.
Absence of food effects on the pharmacokinetics of terfenadine
Authors: Eller Mark G. , Walker Barbara J. , Yuh Lianng , Antony Kelly K. , McNutt Bruce E. , Okerholm Richard A.
Published: October 2006

Administration of terfenadine (Seldane®) immediately after a high fat breakfast slightly affects the rate but not the extent of absorption relative to fasting administration. Mean peak levels of the active metabolite were increased by 13 per cent but delayed by 0·9h while AUC was virtually the same as when terfenadine was administered while fasting. Changes in rate of absorption may be due to delayed gastric emptying and more rapid terfenadine solubilization. In any case, these rate differences are unlikely to be clinically important in the absence of differences in extent of absorption.
Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers
Authors: Thompson Gary A. , Smithers Jacquelyn A. , Kenny Michael T. , Dulworth Jacqueline K. , Kulmala Henrik K. , Yuh Lianng , Lewis Eric W. , Antony Kelly K.
Published: October 2006

Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg−1 in 10 normal, healthy, male volunteers, using a two‐period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg−1 was administered every 12 h as a 30‐min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg−1) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12 mg kg−1, median pharmacokinetic parameters included: steady‐state volume of distribution of 1·4 and 1·21 kg−1; total clearance of 12·2 and 14·0 ml h−1 kg−1; renal clearance of 11·1 and 10·3 ml h−1 kg−1; and terminal disposition half‐life of 159 and 155 h, respectively. No statistically significant dose‐related difference was observed. In addition, a cross‐study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg−1.
Organ distribution and stability of phosphorothioated oligodeoxyribonucleotides in mice
Authors: Goodarzi Goodarz , Watabe Misako , Watabe Kounosuke
Published: October 2006

Results 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

Bioequivalence 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

The 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

The 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

The 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

A 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

Procaterol 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

Obtaining 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

The 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

In 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

Specific 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

Despite 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

The 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

The 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

The 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

Recently, 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

The 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

Rilmazafone (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.
Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects
Authors: De Vries M. H. , Van Harten J. , Van Bemmel P. , Raghoebar M.
Published: October 2006

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three‐way cross‐over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and Cmax‐dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose‐dependent manner in the dose range between 25 and 100 mg; t1/2 and Tmax showed no significant differences among treatments. Fluvoxamine was well tolerated.
Nonlinear elimination and hepatic concentration of conjugation‐ metabolite of valproate in guinea‐pigs
Authors: Yu Hsiu‐Ying , Wu Mei‐Sue , Shen Yu‐Zen
Published: October 2006

The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea‐pigs placed on various (0.08‐9 μmol ml−1 = 11–1303 μg ml−1) steady‐state plasma concentrations (Css) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 μmol ml−1 (88 μg ml−1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (Vmax) and the Michaelis‐Menten constant (Km) for the primary (Vmaxl, Kml) and the secondary (Vmax2, Km2) pathways were Vmaxl = 1.52 μmol min −1kg−1, Kml = 0.15 μmol ml−1, Vmax2 = 24.98 μmol min −1 kg−1 and Km2 = 11.70 μmol ml−1, respectively. The Kml value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose‐dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (fu), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The Km value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the Kml value. These results implied that the primary metabolic parameters may describe the conjugation pathway which is nonlinear within the clinical therapeutic concentration range.
Pharmacokinetics and bioavailability of medroxyprogesterone acetate in the dog and the rat
Authors: Smith D. , Enever R. , Dey M. , Latta D. , Weierstall R.
Published: October 2006

Medroxyprogesterone acetate (MPA) has been administered to rats and dogs. Dogs received single oral doses of 2.5, 5, and 10 mg MPA and a single intravenous dose of 1 mg MPA. Rats received single oral doses of 0.2, 1, 5, and 20 mg kg−1 MPA and multiple oral doses (14 daily doses) of 0.2, 5, and 20 mg kg−1 MPA. Dog plasma MPA levels from the intravenous dose were characterized by a triexponential decay with disposition half‐lives of 0.3, 1.8, and 21.6 h. A Loo‐Riegelman analysis of the dog plasma MPA levels from oral doses indicated absorption was not a simple first‐order process. The Weibull Function was used to characterize the absorption kinetics of MPA. The oral absorption of MPA in dogs appears to be dose‐linear over the dosage range studied, and the absolute bioavailability was estimated at 27 per cent. Rat plasma MPA levels from single and multiple oral doses were analyzed by a non‐compartmental approach. AUC and Cmax values were not dose‐linear over the dosage range studied; indicative of the self‐induced metabolism of MPA. Exposure of similar dosages of MPA to both the rat and the dog resulted in similar plasma profiles and pharmacokinetics.
Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase isozymes by repeated cyanamide administration: Pharmacokinetic‐pharmacodynamic relationships
Authors: Piera Juan Pruñonosa , Obach Rosendo , Sagristá Maria Luisa , Bozal Jorge
Published: October 2006

The inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (ALDH) isozymes was studied in apparent steady‐state conditions after repeated intra‐peritoneal cyanamide administration. The low‐Km mitochondrial ALDH isozyme was more susceptible to cyanamide‐induced inhibition (DI50 = 0.104 mg kg−1) than the high‐Km isozyme (DI50 = 8.52 mg kg−1), with almost complete inhibition occurring at 0.35 mg kg−1 total cyanamide administered for the low‐Km isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high‐Km ALDH were established by means of the sigmoid Imax model. The effect of dosing rate on the plasma concentration of cyanamide at apparent steady‐state showed non‐linearity, indicating that clearance or first‐pass metabolism of cyanamide during its absorption after intraperitoneal administration did not remain constant throughout the range of doses studied.
The use of a nonlinear absorption model in the study of ascorbic acid bioavailability in man
Authors: Piotrovskij V. K. , Kállay Z. , Gajdoš M. , Geryková M. , Trnovec T.
Published: October 2006

A two‐compartment disposition model of ascorbic acid (AA) pharmacokinetics with saturable and time‐constrained intestinal absorption was developed. The model was fitted to pharmacokinetic data obtained after oral administration to nine healthy volunteers of two effervescent dosage forms differing in AA content: Celaskon 60 mg (CK60) and Celaskon 500 mg (CK500). It was demonstrated that in the case of CK500 less than 30% of the dose was absorbed as compared with CK60. Parameters of the AA nonlinear absorption kinetics were assessed by simultaneous fitting of mean concentration—time data for both doses and placebo. The relatively short duration of absorption found (3.2 h) can explain the failure of past attempts to increase the AA bioavailability using sustained‐release dosage forms. Model simulation showed that the ingestion of 60 mg with 3–4 h intervals is optimal for maximal bioavailability of AA.
Toxicokinetic approach for evaluating respiratory depression effect of aminoglycoside antibiotics: Species differences in drug susceptibility
Authors: Komiya Izumi , Mitomi Nayu , Kuribayashi Takashi , Takata Hiromi
Published: October 2006

The respiratory depression effect of aminoglycoside antibiotics was studied by a toxicokinetic approach, and species differences in drug susceptibility were elucidated based on plasma concentrations. An allometric relationship was obtained between total body clearance of arbekacin, a novel aminoglycoside antibiotic, and animal body weight. The power was 0.714, less than unity, which means smaller animals have higher ability to eliminate the drug from the body and need higher doses to attain a certain steady‐state plasma concentration. When the infusion rate of arbekacin was altered, the total dose required to cause the toxicologic endpoint for respiratory depression (60 per cent loss of respiratory rates) changed greatly, but the plasma concentration of arbekacin at the toxicologic endpoint remained at almost a constant level. The concentration at the toxicologic endpoint was similar for all of the animal species examined and was 650–950 μg ml−1, even though the total dose required to cause the toxicologic endpoint varied greatly among the animal species. These findings suggest that the toxicologic effect compartment for respiratory depression is indistinguishable from the plasma compartment, and that species differences in the total dose are due to differences in pharmacokinetics of the drug, mainly in the total body clearance, but not to differences in intrinsic susceptibility to the drug.
Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans
Authors: Vree Tom B. , Van Den Biggelaar‐Martea Magdalena , Verwey‐Van Wissen Corrien P. W. G. M. , Vree Jeroen B. , Guelen Pieter J. M.
Published: October 2006

The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O‐desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 ± 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p <0.0153). Naproxen acyl glucuronide accounts for 50.8 ± 7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5 ± 2.0 per cent, O‐desmethylnaproxen acyl glucuronide for 14.3 ± 3.4 per cent, and its isoglucuronide for 5.5 ± 1.3 per cent (n = 10; 100 h collection period). Naproxen and O‐desmethylnaproxen are excreted in negligible amounts ( <1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0–5.5) in order to stabilize the acyl glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O‐desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O‐desmethylnaproxen acyl glucuronide and 42 per cent for O‐desmethylnaproxen isoglucuronide.
Bumetanide binding to normal albumins and to albumin in renal failure
Authors: Howlett M. R. , Auld W. H. R. , Murdoch W. R. , Skellern G. G.
Published: October 2006

Binding of bumetanide, a loop diuretic, to partially purified albumins from renal failure patients (RF‐HA), and healthy subjects (N‐HA), human serum albumin (HSA) and defatted‐HSA (D‐HSA), was studied with equilibrium dialysis at a constant albumin concentration and various ligand concentrations.

Binding parameters (n and K) were estimated from Scatchard plots and with a nonlinear two‐binding site model computer program, assuming two classes of independent sites. The binding capacities (n1K1) decreased in the order N‐HA>RF‐HA>D‐HSA>HSA. Computer estimates of K1 for the partially purified albumin preparations were not markedly different. However, the graphical estimate of K1 for N‐HA was greater than that for RF‐HA. When the degree of binding (r) was plotted as a function of the logarithm of the free bumetanide concentration, an asymptotic plateau was not observed, indicating that the protein binding sites were not saturated. Consequently, the calculated binding estimates may not adequately describe the binding of bumetanide.
Metabolism and disposition of EXP631—A novel antidepressant analgesic
Authors: Wong Y. N. , Burcham D. L. , Huang S.‐M. , Quon C. Y.
Published: October 2006

EXP631, 4‐(3‐thienyl)‐α,α, 1‐trimethyl‐4‐piperidinemethanol hemi‐fumarate salt (I), is a centrally acting non‐opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5–20 mg kg−1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92–131%. The pharmacokinetics was dose independent as measured by either Cmax or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N‐desmethyl metabolite (II) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.
Pharmacokinetics of intravenous and epidural ropivacaine in the rhesus monkey
Authors: Katz Jeffrey A. , Sehlhorst Constance S. , Thompson Gary A. , Denson Donald D. , Coyle Dennis , Bridenbaugh Phillip O.
Published: October 2006

Ropivacaine is a new long‐acting amide local anesthetic which is possibly less cardiotoxic than bupivacaine. The absorption and disposition of ropivacaine were characterized in six rhesus monkeys in an open two‐way crossover study following intravenous and epidural administration. For these studies, animals were anesthetized for placement of intravenous and intraarterial catheters. For the epidural studies, a PE‐10 catheter was also inserted 3 cm into the lumbar epidural space. After recovery from anesthesia, animals received ropivacaine 1 mg kg−1 intravenously over 1 min or 10 mg of ropivacaine epidurally (two 1 ml doses of 0.5, 5 min apart), and arterial blood samples were obtained over 5 h. Serum ropivacaine concentrations were determined by gas chromatography with NP detection. Concentration—time data following i.v. and epidural administration were fitted simultaneously. Initial parameter estimates were obtained by analyzing each route separately. Input rates and their corresponding extent of absorption were estimated using deconvolution.

Mean (±SD) disposition parameters included: Vss = 1.11±0.198 1kg−1; CL = 0.711 ± 0.158 1 h−1 kg−1; t1/2,z = 2.07 ± 0.438 h. Mean (± SD) absorption parameters included: F1 = 0.506 ± 0.221; t = 0.060 ± 0.078 h; F2 = 0.444 ± 0.182; t = 6.45 ± 11.09h. Ropivacaine's biphasic absorption and bioavailability are similar to those of other amide local anesthetics. The biphasic absorption may be related to partitioning into fat or regional changes in blood flow induced by the drug.
Biotransformation and urinary excretion of 4‐substituted amphetamines in pregnant mice
Authors: Foster Brian C. , Litster Dionne L. , Buttar Harpal S. , Dawson Brian , Zamecnik Jiri
Published: October 2006

The urinary elimination of 4‐hydroxyamphetamine (PHA) and a series of homologous 4‐alkoxy‐substituted amphetamines and their metabolites was examined after single and multiple oral administration to pregnant and non‐pregnant mice.

The metabolic profile and extent of biotransformation in a series of alkoxy analogues were affected by the size of the alkoxy side chain, multiple dosing and pregnancy. There were increased recoveries of both the substrate and the conjugated derivative of PHA during gestation. The major metabolic routes observed were O‐dealkylation, conjugation, and aliphatic hydroxylation of the propoxy side chain. There was some evidence of oxidative deamination. Pregnancy did not alter the profile of the major metabolites detected by GLC and NMR spectroscopy.
Single‐dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers
Authors: Sandouk P. , d'Yvoire M. Bouvier , Chretien P. , Tillement J. P. , Scherrmann J. M.
Published: October 2006

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half‐life (t1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl® tablets have an adequate in vivo dissolution profile.
Comparative bioavailability of two oral formulations of ketorolac tromethamine: Dolac® and Exodol®
Authors: Flores‐Murrieta Francisco J. , Granados‐Soto Vinicio , Castañeda‐Hernández Gilberto , Herrera Jorge E. , Hong Enrique
Published: October 2006

The bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol® and Dolac®, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma‐concentration‐against‐time curves were constructed. Maximal plasma concentration and AUC0‐24. values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for Cmax and from 85 to 118% for AUC0‐24. It is concluded that the two assayed formulations are bioequivalent.
Disposition of 14C‐dapoxetine in rats: Complementary experiments with whole‐body autoradiographic and tissue dissection techniques
Authors: Bernstein J. R. , Manzione B. M. , Pohland R. C. , Franklin R. B.
Published: October 2006

Tissue distribution studies, utilizing whole‐body autoradiography and organ dissection techniques, were conducted in male Fischer 344 rats following the oral administration of 14C‐dapoxetine HCl, a potent serotonin reuptake inhibitor. The preliminary study using whole‐body autoradiography proved invaluable in locating radioactivity in an organ not usually harvested in a tissue distribution study, namely the preputial gland. Selected organs, based on whole‐body autoradiography findings, were dissected from rats and analyzed for radiocarbon content by liquid scintillation counting and for parent drug and N‐dealkylated metabolites by extraction and HPLC analysis. Highest concentrations of radiocarbon were observed in the organs of absorption and elimination (ileum, cecum, stomach, duodenum, liver, colon, and kidney) but notable quantities were observed in the lung and preputial and Harderian glands. Most tissues had returned to background radioactive levels 72 h after dosing but persistent concentrations of radiocarbon were present in the preputial gland and liver one week after the single dose of 14C‐dapoxetine.

Analysis by HPLC demonstrated the presence of parent drug and N‐desmethyl metabolite (nor‐dapoxetine) in those organs examined; however, the majority of the radioactivity remained unidentified.