bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioavailability and reversible metabolism of prednisone and prednisolone in man
Authors: Garg Varun , Jusko William J.
Published: October 2006

The pharmacokinetics of prednisone and prednisolone was examined in 12 healthy male subjects to assess the bioavailability and the parameters of reversible metabolism between the two steroids. After an oral prednisone dose of 0.8 mg kg−1 and an intravenous prednisolone dose of 0.66 mg kg−1, the bioavailability was found to be about 62%. The fraction of the dose recovered in the urine as the hydroxylated metabolites of prednisone and prednisolone was lower after the oral prednisone dose, suggesting that poor absorption of prednisone was the main cause of the low bioavailability. There was a high degree of interconversion between prednisone and prednisolone with 76% of the dose being recycled. The formation clearance of prednisolone from prednisone is much greater than the formation clearance of prednisone from prednisolone or the irreversible elimination clearances of the two steroids. The possible dose dependences of bioavailability and interconversion may be important factors in prednisolone therapy.
The effect of multiple doses of ranitidine on the pharmacokinetics and metabolism of diltiazem in dogs
Authors: Yeung Pollen K. F. , Mosher Susan J. , Landriault Hélène
Published: October 2006

In order to determine the potential pharmacokinetic drug interaction between ranitidine and diltiazem (DTZ), each of ten male beagle dogs, age 2·7–4·0 years, weight 13–16 kg, received a single oral dose of sustained release DTZ with and without previous multiple oral doses of ranitidine (150 mg bid for five doses). The dog was selected as the animal model because the pharmacokinetics and metabolism profiles of DTZ are similar to those in humans and because sustained release DTZ capsules can be administered with ease to this species. Following the oral dose of DTZ, blood samples (5 ml each) were obtained via a cephalic vein at 0 (just before dosing), 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, 36, and 48 h after the dose. Urine samples were collected for 48 h post dose. Plasma and urine concentrations of DTZ and its major metabolites N‐monodesmethyl DTZ (MA), deacetyl DTZ (M1), and deacetyl N‐monodesmethyl DTZ (M2) were determined by HPLC. Pharmacokinetic parameters were calculated by non‐linear curve fitting, and the effect of ranitidine was evaluated by two‐factor analysis of variance (ANOVA). Pre‐treatment of the animals did not significantly alter the disposition of DTZ (p >0·05). Similar to the results reported in clinical studies, there were large variations in the plasma and urine concentrations of DTZ and its major metabolites among the beagle dogs. The effect of ranitidine on the disposition of DTZ was highly variable.
Kinetic modelling of liposome degradation in serum: Effect of size and concentration of liposomes in vitro
Authors: Harashima Hideyoshi , Ochi Yoshihito , Kiwada Hiroshi
Published: October 2006

The purpose of this study is to propose a new method for quantitative evaluation of liposome degradation in serum. The time course of liposome degradation in rat serum was monitored continuously, using 6(5)‐carboxyfluorescein as an aqueous phase marker. The degradation curves exhibited three characteristic phases: lag time, degradation, and plateau. This curve was described by a kinetic model with three parameters: lag time (τ), first‐order degradation rate constant (k), and maximum degradation (α). The rate and extent of the degradation of liposomes were evaluated separately in terms of k and α, respectively. The effects of size and concentration of liposomes on their degradation kinetics were examined using this method. Both k and α increased with increasing liposomal size. The increased affinity of larger liposomes for complement was suggested to increase both k and α. On the other hand, α decreased with increasing liposomal concentration without altering k. The decreased extent of degradation was considered to result from the depletion of complement components. There was no significant effect of size and concentration of liposomes on τ. Quantitative evaluation of the rate and extent of degradation of liposomes will provide deeper insights into the interaction between liposomes and serum components, and basic information on liposomes as potential drug carriers.
A single‐dose comparison of the bioavailabilty of aluminium from two formulations of sucralphate in normal volunteers
Authors: Conway E. L. , O'Callaghan C. , Drummer O. H. , Howes L. G. , Louis W. J.
Published: October 2006

The oral bioavailability of aluminium was compared after administration of 1 g sucralphate as either a tablet or a suspension (1 g/5 ml) in a crossover study in 16 healthy volunteers. Aluminium levels were detectable in all subjects pre‐dose (21.4±8·8 μg 1−1 before tablet; 21·4±7·4 μg 1−1 before suspension) and there was a measurable increase in the plasma concentrations of aluminium in all subjects after administration of the suspension, and in 14 of the subjects after administration of the tablet formulation, with Cmax reached within the first 8 h in most subjects. Plasma levels were still elevated 72 h after dosing. The variability in plasma levels of aluminium was significantly higher after administration of the suspension (CV 39–53%) than after administration of the tablet (CV 29–44%), reflecting greater absorption of aluminium from the suspension formulation in three subjects. Similarly, the variance of the Cmax, AUC(0–72 h), and AUC(0–∞) (for both the raw data and the baseline adjusted data) were all higher for the suspension than for the tablet. A point estimate of the difference of the pharmacokinetic parameters (determined from the median of the arithmetic Walsh averages) indicated little or no difference in Cmax, Tmax, or AUC(0–∞) in the two formulations. In summary, the performance of the suspension formulation of sucralphate is more variable than the tablet formulation in vivo and some patients may therefore have higher circulating levels of aluminium on therapy with the suspension formulation.
Predicting the hepatic clearance of xenobiotics in humans from in vitro data
Authors: Hoener Betty‐Ann
Published: October 2006

Values for Vmax and Km determined during the in vitro metabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CLH) of the xenobiotic to that metabolite. The calculated CLH values were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6‐hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110±77 mL min−1 and 110 mL min−1, respectively. For the 6β‐hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13±15 mL min−1 and 13 mL min−1; 758±282 or 829±283 mL min−1 and 875 mL min−1; and 284±176 mL min−1 and 294 mL min−1, respectively. An increase to 72±25 mL min−1 in the CLH of cortisol to 6β‐hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method and its limitations are discussed.
Arterial and venous blood sampling in pharmacokinetic studies: Azosemide in rabbits
Authors: Lee Sun H. , Shin Wan G. , Lee Myung G. , Kim Nak D.
Published: October 2006

The pharmacokinetics of azosemide were evaluated simultaneously using both arterial and venous plasma data in six rabbits after a rapid 5 s intravenous bolus dosing. Initial arterial to venous ratios at 5 s after injection were the highest with values of 81.1, 67.3, 58.7, 530, 2660, and 10.5 for rabbits 1–6, respectively. Both curves decayed, paralleling each other at the terminal phase, with the venous levels higher than the arterial levels by 15.3, 31.9, 34.1, 40.7, 30.5, and 16.5% for rabbits 1–6, respectively. An exponential term with a negative coefficient was used to account for the short and steep rising phase of venous plasma levels after injection. Detailed analysis showed significant differences in various pharmacokinetic parameters, such as initial volume of distribution, apparent volume of distribution at steady state, and mean residence time based on arterial or venous data. A plot of 1/Q (urine flow rate) versus l/CLR (renal clearance) of azosemide yielded a straight line in six rabbits, indicating that the CLR of azosemide is urine flow dependent in rabbits.
Influence of γ‐aminobutyric acid on baclofen intestinal absorption
Authors: Nácher A. , Polache A. , Moll‐Navarro M. J. , Plá‐Delfina J. M. , Merino M.
Published: October 2006

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by β‐alanine and therefore mediated, at least in part, by the β‐aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a γ‐aminoacid model compound, γ‐aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease as the GABA concentration increases, with a limiting value of 0.65 h−1 (±0.01). A partial competitive inhibition or complete competitive inhibition in the presence of a passive component could define the interaction phenomena between the two substances. Kinetic absorption parameters for GABA in the presence and absence of baclofen (Ki = 5.67 ± 1.54, Km = 3.87 ± 0.63) suggest the existence of more than one intestinal carrier system for baclofen or GABA.
The pharmacokinetics of methotrexate after intravenous administration of methotrexate‐loaded proliposomes to rats
Authors: Park Jeong M. , Ahn Byung‐N. , Yoon Eun J. , Lee Myung G. , Shim Chang‐K. , Kim Chong‐K.
Published: October 2006

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX‐loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg−1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (Cp), the area under the plasma concentration‐time curve (AUC, 639 versus 913 μg min mL−1), the terminal half‐life (t1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (Vss, 98.1 versus 2800 mL kg−1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min−1 kg−1), renal clearance (CLR, 4.49 versus 2.78 mL min−1 kg−1), non‐renal clearance (CLNR, 7.50 versus 5.99 mL min−1kg−1), and the amount of MTX excreted in urine (Xu, 808 versus 685 μg, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX‐loaded liposomes (formed immediately after hydration of MTX‐loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and Vss from treatment II), and MTX is slowly released from MTX‐loaded liposomes (higher t1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher Cp and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t1/2, MRT, and Vss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX‐loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX‐loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX‐loaded proliposomes when incubated with phosphate‐buffered saline (PBS), rat plasma, or rat liver homogenate.
The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone—a novel galactose single‐point method as a measure of residual liver function
Authors: Hu Oliver Yoa‐Pu , Tang Hung‐Shang , Chang Ching‐Ling
Published: October 2006

Cefoperazone is a semisynthetic cephalosporin antibiotic containing a piperazine side chain, which results in antipseudomonal activity. Unlike the other cephalosporins, it is mainly cleared by the liver (60–80%) and it may be more sensitive to changes in the liver function and/or plasma protein binding than other cephalosporins, which are not primarily cleared by the liver. In order to study the influence of chronic lobular hepatitis on the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 normal, healthy volunteers and 16 subjects with chronic lobular hepatitis. In each volunteer or patient, a novel galactose single‐point (GSP) method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were also performed as a measure of residual liver function. Cefoperazone was administered intravenously over a period of 3–5 min. Blood and urine samples were collected at appropriate intervals after drug administration and stored at −30°C until high‐pressure liquid chromatographic (HPLC) analysis.

The cefoperazone hepatic clearance, mean residence time, and renal clearance in hepatitis patients were significantly different from those of normal healthy volunteers, whereas the plasma protein binding was unaltered between the two groups. Urinary excretion of cefoperazone showed a highly significant increase in patients, 23.95 ± 5.06% and 37.54 ± 13.61% for normal men and hepatitis patients respectively. Hepatic clearance and fraction excreted in urine significantly correlated with values of GSP and MGEC respectively (p <0.05). These results suggest (i) cefoperazone kinetics was significantly altered in patients with chronic lobular hepatitis; (ii) GSP, a novel simple, clinically useful quantitative liver function test, can predict the cefoperazone hepatic clearance in patients with liver dysfunction.
Relative bioavailability of two oral formulations of navelbine in cancer patients
Authors: Zhou X. J. , Zhou‐Pan X. R. , Favre R. , Rahmani R.
Published: October 2006

A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two‐way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (Cmax) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0–∞) AUC.
Variability in the disposition of chlorzoxazone
Authors: De Vries Jantine D. , Salphati Laurent , Horie Seichi , Becker Charles E. , Hoener Betty‐Ann
Published: October 2006

Chlorzoxazone is 6‐hydroxylated by cytochrome P450 2E1 (CYP 2E1), which bioactivates many toxic and carcinogenic molecules. Seventeen volunteers of varying age, ethnicity, and gender received a 250 mg tablet of chlorzoxazone and their blood and urine were sampled frequently for 8 h. V/F = 42 ± 21 L and CL/F = 412 ± 120 mL min−1. Comparison of these values with a study by other investigators using a suspension dosage form suggested that relative Ftablet ± 0.7. The fraction excreted in the urine as 6‐hydroxychlorzoxazone (f2,6‐OH) was 0.39 ± 0.20 and that portion of the total CL accounted for by CYP 2E1‐mediated metabolism (CL6‐OH) was 163 ± 95 mL min−1. Thus, while V/F and CL/F varied by factors of less than five, fe,6‐OH varied 16‐fold and CL6‐OH varied 28‐fold. These results suggested that there was considerable inter‐individual variability in the metabolism of chlorzoxazone to 6‐hydroxychlorzoxazone. This variability will significantly affect the construction of physiologically based pharmacokinetic models that use the 6‐hydroxylation of chlorzoxazone as a marker for an individual's CYP 2E1 phenotype.
Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin three different parenteral administrations compared in 30 arthroplasties
Authors: Ferrero Miguel M. Alvarez , Vree Tom B. , Van Ewijk‐Beneken Kolmer Eleonora W J. , Slooff Tom J. J. H.
Published: October 2006

The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin.

Six groups of five patients participated in the study. The first three groups (A–C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D–F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously.

Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients.

Large inter‐individual variation in bone concentration was observed.

The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.
Pharmacokinetic profile of conjugated verrucarol urinary metabolites in dogs
Authors: Barel Shimon , Yagen Boris , Bialer Meir
Published: October 2006

The pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg−1).

The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32–60% for verrucaryl glucuronides and 32–47% for verrucaryl sulphates. These urinary conjugated metabolites were analyzed quantitatively following their enzymatic hydrolysis. The half‐life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half‐life calculated from the plasma data of the parent compound.
Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV‐1 protease inhibitor, KNI‐272, in rats after intravenous administration
Authors: Kiriyama A. , Fujita K. , Takemura S. , Kuramoto H. , Kiso Y. , Takada K.
Published: October 2006

The pharmacokinetic (PK) characteristics of KNI‐272, a potent and selective HIV‐1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI‐272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI‐272, were examined. After IV administration of 10.0 mg kg−1 KNI‐272, the mean terminal elimination half‐life, t1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CLtot, was 15.1 ± 1.2 mL min−1 and the distribution volume at steady state, Vd,ss, was 3790±280 mL kg−1. On the other hand, after 1.0mg kg−1 IV administration, td,ss, was 3.04±0.11 h, CLtot was 15.9±0.2mL min−1, and Vd,ss was 6950±600 mL kg−1. The PK parameters of KNI‐272 after IV administration showed that the disposition of KNI‐272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg−1. Using an equilibrium dialysis method, the plasma binding of KNI‐272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL−1, 0.888 ± 0.008 μg mL−1, and 0.470±0.55 μg mL−1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg−1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg−1 dose, respectively. The renal clearance (CLR) and the biliary clearance (CLB) were calculated to be 0.191 and 0.256mL min−1 for 1.0mg kg−1, and 0.0248 and 0.215 mL min−1 for 10.0 mg kg−1, respectively. When comparing these values with the CLtot values, the urinary and biliary excretion of KNI‐272 are minor disposition routes.
A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. in vitro and in vivo studies in beagle dogs
Authors: Vattikonda Chandra S. , Ritschel Wolfgang A.
Published: October 2006

The purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F−). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F−, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F− followed a two‐compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.
Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse
Authors: Uchegbu Ijeoma F. , Turton John A. , Double John A. , Florence Alexander T.
Published: October 2006

Niosomes (non‐ionic surfactant vesicles) prepared from C16G2 (a hexadecyl‐diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg−1. Free drug was given at 10.0 mg kg−1 by the intraperitoneal route. At a dose level of 10.0 mg kg−1, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg−1 dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg−1, mean peak plasma concentrations of the drug showed a tendency to be dose‐related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg−1, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p <0.05). When doxorubicin was given in niosomes at 2.5, 5.0 and 10.0 mg kg−1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac‐tissue concentration was higher in animals receiving the free drug at 10.0 mg kg−1 intraperitoneally than in mice given intaperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin‐containing niosomes intraperitoneally at 5.0 and 10.0 mg kg−1, and at post‐mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg−1, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg−1. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg−1 and at a dose volume of 0.2–0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg−1 when the formulation was administered with the higher dose volume of 1.8–2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given itravenously at 12.0 mg kg−1.
Variable gastric emptying and discontinuities in drug absorption profiles: Dependence of rates and extent of cimetidine absorption on motility phase and pH
Authors: Langguth Peter , Lee Kathleen M. , Spahn‐Langguth Hildegard , Amidon Gordon L.
Published: October 2006

The influence of various fasting‐state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double‐peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive‐migrating‐motor‐complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase‐I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half‐life, two concentration maxima (double peaks) were found in 12% of the simulated concentration‐time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 <30 min. When cimetidine was administered to dogs as a duodenal infusion in the active andquiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi‐segmental input (one‐ to 3‐lag‐time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration‐against‐time profiles and that it plays a role with respect to double‐peak occurrence, although it is only one of several causative factors.
The influence of pregnancy on the biotransformation and urinary excretion of methoxyphenamine in mice
Authors: Foster Brian C. , Wilson D. Lynden , Cyr Terry D. , Moffatt James , Buttar Harpal S.
Published: October 2006

The urinary elimination of methoxyphenamine (MPA) and its metabolites in underivatized samples was examined after single and multiple oral administration to pregnant and non‐pregnant mice by GLC and GLC—MS.

The major metaboliteO‐desmethylmethoxyphenamine (ODMP), along with lesser amounts ofN‐desmethylmethoxyphenamine (NDMP) and 2‐hydroxyamphetamine (2OH), were the only metabolites detected in urine extracts of pregnant and non‐pregnant mice. 5‐Hydroxymethoxyphenamine (5HMP) was not detected. Enzyme hydrolysis did not increase the recovery of either substrate or metabolites in either the pregnant or non‐pregnant animals. The results show that MPA metabolism in the Swiss—Webster mouse is distinctly different from that seen in man and other laboratory animals.

The mean MPA:ODMP ratio in day‐6 urine from pregnant mice after a single dose was 0.31 ± 0.04. The NDMP:ODMP ratios were less than 0.10 in all samples. Non‐pregnant mice urine had equivalent amounts of MPA, NDMP, ODMP, and 2OH after multiple dosing.

While multiple dosing and pregnancy did not alter either the urinary recovery or profile of the metabolites detected, there was a linear decrease in the MPA:ODMP ratio during gestation.

MPA was extensively metabolized to ODMP in the male mice, and the MPA:ODMP ratio of 0.41 was slightly higher than that observed in the pregnant and non‐pregnant females.
An in vitro study of the influence of a drug's molecular weight on its overall (Clt), diffusive (Cld) and convective (Clc) clearance through dialysers
Authors: Mac‐Kay M. Valera , Fernandez I. Perez , Carranza J. Herrera , Burson J. Sanchez
Published: October 2006

The dialyser clearance of a drug is the sum of two components: one diffusive, arising from the concentration gradient across the membrane, and the other convective, arising from the ultrafiltration of plasma water, produced by the increases in hydraulic pressure that the membrane undergoes.

To demonstrate the importance of these clearnces during haemodialysis, this study analyses the influence of a drug's molecular weight on them.

To this end, an experimental study of dialysis in vitro was carried out to determine the clearances, in aqueous solution, of five drugs of increasing molecular weights (theophylline, quinidine, tobramycin, digoxin, and vancomycin), using two series of dialysers with the same type of membrane (Cuprophan®), differing in effective surface area and ultrafiltration coefficient.

From the data obtained in this study, the importance of quantifying convective clearance during haemodialysis becomes apparent since if it is not taken into account errors of up to 20% and more may be made. This is particularly so if the drug is of high molecular weight and if a high filtration rate is being used.
An evaluation of numerical integration algorithms for the estimation of the area under the curve (AUC) in pharmacokinetic studies
Authors: Yu Zhiling , Tse Francis L. S.
Published: October 2006

Six numerical integration algorithms based on linear and log trapezoidal methods as well as four cubic‐spline methods were proposed for estimation of area under the curve (AUC). These six different algorithms were implemented using IMSL/IDLTM command language and evaluated using data simulated under five different dosing conditions and two different sampling conditions. Comparisons between AUC estimations using these six different algorithms and the theoretical results were made in terms of both overall AUC values and the superimposability of the concentration‐time profiles. In well designed studies with ample data points, the algorithm based on IMSL/IDLTM function CSSHAPE with concavity preservation gave the best performance. In contrast, when the frequency of blood collection was limited, the algorithm based on the log trapezoidal rule proved to be stable with reasonable accuracy, and is recommended as the practical method for numerical interpolation and integration in pharmacokinetic studies. Algorithms based on the combination of the log trapezoidal rule and cubic‐spline methods using IMSL/IDLTM function CSSHAPE can be developed to enhance overall performance.
Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs
Authors: Gómez M. Lisbeth E. , Lehmann F. Pedro A.
Published: October 2006

HEPP (D, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg−1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half‐life (t1/2β) was the same after the three doses (3.4±0.15h) and the mean half‐lives of the distribution phase (t1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg−1 respectively). The mean AUC0‐∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL−1, respectively, showing a linear increase. The individual values of AUC0‐∞ corrected for the administered dose (AUC0‐∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL−1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (Vss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg−1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min−1 kg−1) showed significant differences between doses. The values of Vss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC0‐∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.
Kinetic modelling of liposome degradation in peritoneal macrophages
Authors: Harashima Hideyoshi , Hirai Noriko , Kiwada Hiroshi
Published: October 2006

The objective of this study was to quantify and model the degradation process of liposomes in peritoneal macrophages (PMs). Iodinated albumin (125I‐alb) was chosen to be the marker of liposome degradation. The time course of the degradation of free 125I‐alb after pinocytosis by PMs followed first‐order kinetics with a half‐life of 23 min. The degradation of liposomally encapsulated 125I‐alb was also quantified. Kinetic modelling of liposome degradation indicated the existence of two kinetically different processes, one with a half‐life of 13 min and the other with a half‐life of 7.5 h. Comparing the degradation of liposomal and free 125I‐alb suggested that 125I‐alb was delivered to lysosomes much faster through phagocytosis than pinocytosis. These results indicate that the intracellular degradation kinetics of pinosomes and phagosomes is different. This method can quantify the rate and extent of liposomal degradation in macrophages and provide kinetic information on the intracellular destiny of liposomally encapsulated compounds.
Dose proportionality of stavudine in hiv seropositive asymptomatic subjects: Application to bioequivalence assessment of various capsule formulations
Authors: Kaul Sanjeev , Mummaneni Vanaja , Barbhaiya Rashmi H.
Published: October 2006

The dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single‐dose, randomized four‐way crossover study in 16 asymptomatic HIV‐infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration‐time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, meanCmaxand AUC0‐∞values were in the range of 110.36–889.34 ng mL−1and 246.46–1945.97 h ng mL−1respectively. The meanCmaxand AUC0‐∞of stavudine increased in a dose‐proportional manner. Irrespective of the dose, meanCmaxvalues were observed at a mediantmaxof 0.75 h or less. Meant1/2values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment,Cmaxand AUC0‐∞values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase‐3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose‐normalizedCmaxvalues with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose‐normalized AUC0‐∞values for the 5, 20, and 40 mg capsules relative to the 10 mg phase‐3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.
Pharmacokinetics of dolasetron following single‐ and multiple‐dose intravenous administration to normal male subjects
Authors: Shah Ajit , Lanman Robert , Bhargava Vijay , Weir Scott , Hahne William
Published: October 2006

Dolasetron, AnzemetTM, a 5‐hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto‐reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg−1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg−1 d−1 on days 2–9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half‐life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20–4.43 mL min−1 kg−1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single‐dose pharmacokinetics of this metabolite.
The influence of food intake on the effect of two controlled release formulations of furosemide
Authors: Paintaud G. , Alván G. , Eckernäs S.‐Å. , Wakelkamp M.
Published: October 2006

Differences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four‐treatment, four‐period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p<0.0001, and the median (range) mean residence time increased from 6.3 (4.1–9.3) to 9.5 (5.9–11.8) h, p <0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p <0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r2 = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.
The influence of pyruvic acid on the pharmacokinetics of sulphadiazine in rabbits
Authors: Hsu Kuang‐Yang , Song Dah‐Jing , Ho Yih
Published: October 2006

During the past few years, acetylation polymorphism has been shown to be a proven, established fact, and N‐acetyltransferase, an enzyme that transfers an acetyl group to the substrate, has been recognized as the main factor in acetylation polymorphism. In a recent study, a significant difference between the acetylation phenotype and plasma pyruvic acid (PA) concentration in rabbits was found. In this report, the influence of PA on the pharmacokinetics of sulphadiazine (SDZ), a drug that has been used in pharmacogenetic studies of acetylation, was studied. By using a loading dose of 300 mg kg−1, and an infusion rate of 7.5 mg min−1 of kg−1 of PA, the concentration of PA reached a steady state (Css∽100 μg mL−1) in 30 min. During PA infusion in rapid‐acetylation rabbits, no significant changes were found in any of the pharmacokinetic parameters for SDZ. However, differences were found in the β half‐life, AUC, clearance, and k10 of SDZ in slow acetylators: the β half‐life decreased from 115.74 ± 12.47 min to 62.96 ± 4.36 min (p < 0.001); AUC decreased from 10 617.38 ± 1179.81 μg mL−1 to 6217.14 ± 391.32 μg min mL−1 (p < 0.001); clearance increased from 0.0044 ± 0.0008 L min−1 kg−1to 0.0068 ± 0.0007 L min−1 kg−1 (p < 0.001); and k10 increased from 0.0090 ± 0.0009 min−1 to 0.0193 ± 0.0028 min−1 (p < 0.005). The reason for this may be that PA influences the elimination of SDZ in slow‐acetylation rabbits.
Absorption of new HIV‐1 protease inhibitor, KNI‐272, after intraduodenal and intragastric administrations to rats: Effect of solvent
Authors: Sugahara M. , Kiriyama A. , Hamada Y. , Kiso Y. , Takada K.
Published: October 2006

KNI‐272 is a tripeptide drug that has a strong pharmacological potential for treating human immunodeficiency virus type 1 (HIV‐1). We have already reported the pharmacokinetic characteristics of KNI‐272 after intravenous and intraduodenal (ID) administrations to rats. In this study, KNI‐272 was administered to rats as a solution and the effect of four kinds of solvent on the bioavailability (BA) of KNI‐272 was determined using rats. The mixtures included propylene glycol (PG) and water (70% PG), a solution of PG (100% PG), a solution of Tween 80 (Tween 80), and a mixture of PG and HCO60, a polyoxyethylated, 60μmol, castor oil derivative (PG:HCO60=7:3). After ID administration to rats at a dose of 50.0 mg kg−1, the mean peak plasma concentrations, Cmax, were 2.58±0.53 (SE) (70% PG), 3.28±0.51 (100% PG), 3.15±0.51 (Tween 80), and 4.66±0.68 μg mL−1 (PG:HCO60). The highest BA, 44.6%, was obtained after ID administration of KNI‐272 dissolved in PG:HCO60. On the other hand, after intragastric (IG) administration of KNI‐272 solution in which the drug was dissolved with PG:HCO60, the Tmax, the Cmax, and the BA were 1.25±0.60h, 2.33±0.65 μg mL−1, and 24.2%, respectively. The Cmax and BA values were equal to half of the values obtained after ID administration of KNI‐272 dissolved in the same solution. In this study, as the PG concentration in the solution increased and the other additives (Tween 80 and HCO60) were coadministered, the BA of KNI‐272 after ID administration increased. These results suggest that, for the development of an oral dosage form of KNI‐272, a non‐ionic surfactant that dissolves in the duodenum or small intestine and that enhances the absorption of this drug from the gastrointestinal tract into the enterocytes is needed.
Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate‐bearing positively charged liposomes to rats
Authors: Kim Myoung M. , Lee Sun H. , Lee Myung G. , Hwang Sung J. , Kim Chong‐K.
Published: October 2006

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (IV) and intramuscular (IM) injection of free MTX (treatment I), freshly prepared MTX‐bearing positively charged liposomes (large unilamellar vesicles), PLUVs (treatment II), and empty PLUVs mixed manually with free MTX (treatment III), 4 mg kg−1 as free MTX to rats, using HPLC assay. After 1 min IV infusion, the plasma concentrations of MTX (Cp), the area under the plasma concentration—time curve (AUC, 173 against 314 μg mL min−1), the terminal half‐life (t1/2, 24.0 against 412 min), the mean residence time (MRT, 13.0 against 324 min), and the apparent volume of distribution at steady state (VSS, 289 against 3370 mL kg−1) were significantly larger, but the total body clearance (CL, 23.1 against 12.8 mL min−1 kg−1), the renal clearance (CLR, 8.38 against 3.09 mL min−1 kg−1), the non‐renal clearance (CLNR, 14.6 against 9.56 mL min−1 kg−1), and the amount of MTX excreted in urine (Xu, 415 against 275 μg) were significantly lower in treatment II than in treatment I. This could be due to the fact that some of the MTX‐bearing PLUVs were entrapped in tissues and the rest were present in plasma (larger MRT and Vss in treatment II), and MTX is slowly released from MTX‐bearing PLUVs (longer t1/2 in treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX in MTX‐bearing PLUVs (larger Cp and AUC and slower CL in treatment II). Saturable formation of 7‐hydroxymethotrexate from MTX was reported in rabbit blood and non‐linear disposition of MTX was also reported in rats and rabbits (lower Xu and CLR in treatment II). After 1 min IV infusion, some pharmacokinetic parameters of MTX, such as AUC, CL, CLR, CLNR, and Xu, were significantly different between treatments I and III, but nonetheless the differences were smaller than those between treatments I and II. After both IV and IM administration, the amount of MTX remaining per gram of tissue or organ in the kidney, stomach, small intestine, and large intestine was significantly smaller in treatment II than in treatment I. Such tissue results imply that the side‐effects of MTX on kidney and GI tract could be reduced after both IV and IM administration of MTX‐bearing PLUVs rather than free MTX. The encapsulation efficiency of MTX in MTX‐bearing PLUVs was 5.47%, and MTX was released slowly from MTX‐bearing PLUVs when incubated in phsophate buffered saline, rat plasma and rat liver homogenates.