Slower Elimination Phase Research Articles

Pharmacokinetics of the potent redox-modulating manganese porphyrin, MnTE-2-PyP 5+, in plasma and major organs of B6C3F1 mice

Mn(III) tetrakis( N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP 5+, a potent catalytic superoxide and peroxynitrite scavenger, has been beneficial in several oxidative stress-related diseases thus far examined. Pharmacokinetic studies are essential for the better assessment of the therapeutic potential of MnTE-2-PyP 5+ and similar compounds, as well as for the modulation of their bioavailability and toxicity. Despite high hydrophilicity, this drug entered mitochondria after a single 10 mg/kg intraperitoneal injection at levels high enough (5.1 μM; 2.95 ng/mg protein) to protect against superoxide/peroxynitrite damage. Utilizing the same analytical approach, which involves the reduction of MnTE-2-PyP 5+ followed by the exchange of Mn 2+ with Zn 2+ and HPLC/fluorescence detection of ZnTE-2-PyP 4+, we measured levels of MnTE-2-PyP 5+ in mouse plasma, liver, kidney, lung, heart, spleen, and brain over a period of 7 days after a single intraperitoneal injection of 10 mg/kg. Two B6C3F1 female mice per time point were used. The pharmacokinetic profile in plasma and organs was complex; thus a noncompartmental approach was utilized to calculate the area under the curve, c max, t max, and drug elimination half-time ( t 1/2). In terms of levels of MnTE-2-PyP 5+ found, the organs can be classified into three distinct groups: (1) high levels (kidney, liver, and spleen), (2) moderate levels (lung and heart), and (3) low levels (brain). The maximal levels in plasma, kidney, spleen, lung, and heart are reached within 45 min, whereas in the case of liver a prolonged absorption phase was observed, with the maximal concentration reached at 8 h. Moreover, accumulation of the drug in brain continued beyond the time of the experiment (7 days) and is likely to be driven by the presence of negatively charged phospholipids. For tissues other than brain, a slow elimination phase (single exponential decay, t 1/2 = 60 to 135 h) was observed. The calculated pharmacokinetic parameters will be used to design optimal dosing regimens in future preclinical studies utilizing this and similar compounds.

Pharmacology and Safety of Tetradecylthioacetic Acid (TTA): Phase-1 Study

This study describes the clinical, hematological, and biochemical safety of tetradecylthioacetic acid (TTA). A total of 18 healthy volunteers were included. Subjects were randomly assigned into 3 groups according to the daily given dose of TTA: group 1 (200 mg), group 2 (600 mg), and group 3 (1000 mg). TTA was given as a single oral dose for 7 consecutive days. Safety was evaluated by following the adverse events, vital signs, and hematological and biochemical parameters in blood and urine samples. Efficacy was estimated through its effects on plasma lipids profile. Few adverse events of mild severity were reported. No clinically significant changes were observed in the hematological or clinical chemical parameters in blood/urine. TTA did not induce significant changes in the blood lipids or free fatty acids, but it did result in an increase in plasma concentration of Delta9 desaturated TTA (TTA: 1n-8). Serum concentration pattern of TTA at day 1 showed a 1.5-hour lag time followed by a rapid absorption and a slower elimination phase. The median peak values were 2.9 mg/L (range, 1.1 to 5.4 mg/L), 11.5 mg/L (range, 4 to 35 mg/L), and 11 mg/L (range, 5 to 25 mg/L), in groups 1, 2, and 3, respectively (P = 0.006). The time to peak levels were 3.5 hours (range, 2.5 to 6.5 hours), 2.5 hours (range, 2.5 to 4.5 hours), and 4.5 hours (range, 2.5 to 12 hours), respectively (P = 0.2). TTA is safe and well tolerated.

Pharmacokinetics, tissue distribution and excretion of a new photodynamic drug deuxemether

Deuxemether was a new photodynamic drug effective for many kinds of solid tumor therapy, which was mainly composed of 3-(or 8-)-(1-methoxyethyl)-8-(or 3-)-(1-hydroxyethyl)-deutero-porphyrin IX (MHD) and 3,8-di(1-methoxyethyl)-deuteroporphyrin IX (DMD). The aims of this study were to elucidate its pharmacokinetic characteristics, tissue distribution, plasma protein binding and excretion properties and underlying mechanisms of deuxemether in rats based on the simultaneous determination of MHD and DMD. The pharmacokinetic profiles of both MHD and DMD in rats after intravenous doses were linear and best fitted to a two compartment model, characterized with a rapid distribution phase (MHD: t 1/2 α, 0.09–0.14 h; DMD: t 1/2 α, 0.07–0.11 h) and a relatively slow elimination phase (MHD: t 1/2 β, 2.03–3.20 h; DMD: t 1/2 β, 2.51–3.20 h). The tissue distributions of MHD and DMD in rats were rather limited as evidenced from their low distribution volume (0.75–1.70 L/kg) and the results of tissue distribution study. Protein binding of MHD and DMD were moderate (65.36–89.99% for MHD; 45.43–76.23% for DMD), independent of drug concentrations and similar between human and rat plasma over a concentration range of 0.50–50.0 μg/mL. Both MHD and DMD were predominantly (>74.1%) eliminated from rats as the parent drugs through the hepatobiliary systems and finally excreted into the feces. The multidrug resistance-associated proteins 2 (MRP2) inhibitors, bromosulfophthalein and probenecid, substantially inhibited the hepatobiliary elimination of MHD and DMD while the P-gp inhibitor digoxin had little effect, suggesting that MRP2 may contribute to the rapid and extensive hepatobiliary excretion of deuxemether. There were no significant differences between MHD and DMD for all pharmacokinetic characteristics studied. In conclusion, this study provided firstly the full pharmacokinetic characteristics and mechanisms of deuxemether, which would be helpful for its clinical regiment design.

Targeting Immune Complex-Mediated Hypersensitivity with Recombinant Soluble Human FcγRIA (CD64A)

Binding of Ag-Ab immune complexes to cellular FcgammaR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcgammaR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA were prepared. Binding of rh-FcgammaRIA to IgG was of high affinity (KD=1.7x10(-10) M), whereas rh-FcgammaRIIA and rh-FcgammaRIIIA bound with low affinity (KD=0.6-1.9x10(-6) M). All rh-FcgammaR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-alpha by cultured mast cells. Local or systemic delivery only of rh-FcgammaRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcgammaRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2gamma of approximately 130 h. The highest percentage of injected radioactivity accumulated in blood approximately liver approximately carcass>kidney. s.c. dosing of rh-FcgammaRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcgammaRIA is an effective inhibitor of type III hypersensitivity.

Effect Of Different Degrees Of Hepatic Dysfunction On The Pharmacokinetics Of Telmisartan

Background: Hypertension is a highly prevalent condition, as well as being one of the most powerful contributors to cardiovascular diseases; hypertension is also the leading cause of death in developed countries. Angitensin II receptor blockers represent a new class of effective and well tolerated orally active antihypertensive agents. Telmisartan is a nonpeptide angitensin II receptor antagonist, used for the treatment of hypertension. Objective: To describe the pharmacokinetics and safety of telmisartan in healthy volunteers and in subjects with different degree of hepatic impairment. Setting: Tanta University Hospitals, Faculty of Pharmacy, Ain Shams University and Faculty of Pharmacy, Tanta University, Egypt. Design: Prospective study. Single oral dose of telmisartan 80 mg was given to 10 healthy subjects served as a control group (group 1), and 20 subjects with hepatic impairment; divided into two groups; group 2(10 patients): patients with mild hepatospleenomegaly and group 3 (10 patients): patients with cirrhosis and ascitis. Plasma samples were collected and analyzed with high performance liquid chromatography (HPLC). Main outcome measures: Cmax, tmax, t 1/2, MRT, AUC0-∞, Cl/F and Vdss Results: The pharmacokinetic profile of telmisartan was characterized by rapid absorption kinetics and a slow terminal elimination phase with mean half life of 25 hours. The maximum plasma concentration and area under the telmisartan plasma concentration-time curve (AUC0-∞} increased in all hepatically impaired subjects compared with healthy volunteers. There was a significant increase in the Cmax and AUC0-∞ of the cirrhotic patients and non significant increase in the patients with mild hepatospleenomegaly compared with the healthy volunteers. There was no change in the half life of telmisartan in all the patients and no adverse events were noticed in the patients during the study indicating the good tolerability of the drug in hypertensive patients with hepatic dysfunction. Conclusion: Lower doses of telmisartan should be considered in cirrhotic patients as well as in the patients with mild hepatitis. Egyptian Journal of Biomedical Sciences Vol. 23 (1) 2007: pp. 257-265

Marked Therapeutic Efficacy of a Novel Polyethyleneglycol-SN38 Conjugate, EZN-2208, in Xenograft Models of Non-Hodgkin's Lymphoma.

Background: The clinical utility of SN38 (10-hydroxy-7-ethyl-camptothecin), the active moiety of CPT-11 (Camptosar®), has been severely compromised due to its poor solubility. EZN-2208 is a novel, water-soluble, polyethyleneglycol (PEG)-SN38 conjugate generated by linking SN38 with a multi-arm high molecular weight PEG, 40k 4-arm-PEG, via a glycine linker. Here, we compare the efficacy of EZN-2208 and CPT-11 in the treatment of animals bearing non-Hodgkin's lymphomas.Methods: The in vitro cytotoxicity of EZN-2208 and CPT-11 were tested in human lymphoma (Raji, Daudi, DoHH2) cancer cell lines using the tetrazolium assay. The pharmacokinetics and maximum tolerated dose (MTD) of EZN-2208 and CPT-11 were evaluated in tumor-free severe combined immunodeficient (SCID) mice and the therapeutic efficacy was evaluated in xenograft models of non-Hodgkin's lymphoma (Raji and Daudi).Results: In vitro, the IC50 of EZN-2208 ranged from 2–20nM and the in vitro potency of EZN-2208 was 30 to 50-fold more than CPT-11. The MTDs of EZN-2208 and CPT-11 in SCID mice were 30 and 60 mg/kg, respectively, when injected as a single dose. When administered in a multiple dose regimen (q2d x 5), the MTDs of EZN-2208 and CPT-11 were 10- and 40 mg/kg respectively. The pharmacokinetic profile of EZN-2208 was biphasic showing a rapid distribution phase (t1/2a =0.6h) and a slow elimination phase (t1/2b =19.3h for conjugate and 14.2h for SN38). In the Raji xenograft model, treatment with a single MTD of EZN-2208 resulted in a 500% improvement in life span (ILS) and 50% cures of animals compared with 19% ILS observed for mice treated with a single MTD of CPT-11. Multiple dose treatment of EZN-2208 resulted in 90% cures of animals compared with 63% ILS and no cures observed for the CPT-11 group. In the Daudi xenograft model, a single injection of EZN-2208 given as early treatment resulted in cures of 100% of animals in contrast to 66% ILS and no cures observed for CPT-11 group. When treatment was delayed, a single MTD of EZN-2208 caused 90% cures of animals, whereas CPT-11 treatment was completely ineffective.Conclusions: EZN-2208 demonstrated excellent efficacy in preclinical models of non-Hodgkin's lymphoma. Ongoing Phase I studies will determine the optimal dose and schedule of EZN-2208.

Pharmacokinetic Analysis of a von Willebrand Factor/Factor VIII (VWF/FVIII) Concentrate in Adults and Children with von Willebrand Disease (VWD).

Introduction: Although widely used for the treatment of VWD, optimal doses of VWF/FVIII concentrates for surgical procedures in patients with VWD need to be determined. Two prospective, multicenter studies were undertaken to evaluate the efficacy and safety in surgery of a VWF/FVIII concentrate marketed in the United States (US; Humate-P®) and the European Union (EU; Haemate-P®) in patients with VWD (Lethagen et al. JTH, 2007). Initially, all patients had pharmacokinetic (PK) studies to guide individual dosing for surgery.Results: In the US study, 41 subjects received 60 IU/kg VWF: RCo, and in the EU study 28 subjects received approximately 80 IU/kg VWF: RCo. At specified time points before and after infusion, median levels, half-life, mean change from baseline and in-vivo recovery (IVR) values were determined for VWF: RCo and FVIII: C. Collagen binding capacity (VWF: CB) was correlated with VWF: RCo; and VWF multimer analyses were also performed. In the US and EU studies, median baseline VWF: RCo levels were 13 (range[r] 6–124) and 8.1 (r 5–58) IU/dL; the highest median post-infusion values were 163 (r 84–330) and 147 (r 53–387) IU/dL. Mean change from baseline in the US study was > 100 IU/dL immediately after the infusion, decreasing to about 10 IU/dL at 48 hours post-infusion. The median terminal half-life of VWF:RCo in the US study was 11.7 (r 3.5–74.9) hours. These results are consistent with early and rapid distribution phase, followed by a much slower terminal elimination phase. The median incremental in vivo recovery (IVR) for VWF: RCo in the US and EU studies was 2.4 and 1.9 IU/dL/IU/kg respectively. In the US and EU studies, median baseline levels of FVIII: C were 39 (r 0.5 to 96) and 33 (r 2–106) IU/dL. Mean change of FVIII: C from baseline in the US study was about 60 IU/dL post-infusion, levels decreasing to slightly above 20 IU/dL at 48 hours post-infusion. Median incremental IVRs for FVIII: C in the US and EU studies were 2.7 and 2.8 IU/dL/IU/kg. Median baseline levels of VWF: CB were 13.0 (r 1.5–101) and 10.4 (r 1.0–84) IU/dL. For the US study, the highest median post-infusion VWF: CB value was 131.5 (r 60–204) IU/dL 15 minutes post-infusion. For the EU study, the highest median VWF: CB value was 147 (r 21–330) IU/dL 30 minutes post-infusion. At 48 hours, levels decreased to near baseline (median: 26.5 [r 10–136] IU/dL in the US study, and 13 [r 2–112] IU/dL in the EU study). Conclusions: VWF: CB values correlated well with VWF: RCo values. Analyses showed that high molecular weight VWF multimers were detectable up to 24 hours post-infusions in all subjects with absent multimers at baseline. The PK data suggest a possibility of slight accumulation of FVIII: C, presumably due to a dynamic stabilization of exogenously injected and endogenously released FVIII. The slow terminal elimination phase of VWF: RCo, compared to shorter distribution phase, suggests a minimal risk of VWF: RCo accumulation, easily managed by adjusting the dosing interval. For surgical coverage, an individual patient's PK results safely guided initial dosing, with subsequent doses based on their clinical and laboratory responses.

Investigation on the absorption kinetics of chlorogenic acid in rats by HPLC

Chlorogenic acid (ChA), a major phenolic compound in the Flos Lonicerae, is widely used in the traditional Chinese medicine practice. The purpose of this study is to report the pharmacokinetic parameters of ChA in rats after oral administration and explore its absorption profile briefly. A two-compartment model was proposed and validated through the program to explain the apparent triphasic phenomenon of ChA in rats after intragastric administration. A rapid absorption and a relatively slow distribution followed by a slower elimination phase were observed. At the administered doses of 200, 400 and 600 mg/kg, the values of absorption half-life (t 1/2 Ka) were 10.23, 18.66 and 28.13 min. The values of distribution half-life (t1/2) were 12.35, 31.04 and 39.19 min. And the values of elimination half-life (t1/2P) were 231.64, 337.23 and 420.81 min. The volume of distribution at the three doses were 55.26, 35.56, 32.22 L/kg, respectively. The AUC0-->infinity (area under the concentration-time curve) was not proportional to the administered dose. In the range of the doses examined, the absorption pharmacokinetics of ChA in rats was based on nonlinear kinetics.

In vivo evaluation of lipid nanocapsules as a promising colloidal carrier for paclitaxel

Paclitaxel-loaded lipid nanocapsules (PX-LNC) exhibit interesting in vitro characteristics with improved antitumoral activity compared with free PX formulation. Biodistribution studies were realized with the use of 14C-trimyristin ( 14C-TM) or 14C-phosphatidylcholine ( 14C-PC) whereas antitumoral activity of PX-LNC formulations was based on the animal survival in a chemically induced hepatocellular carcinoma (HCC) model in Wistar rats. Blood concentration–time profiles for both labeled 14C-TM-LNC and 14C-PC-LNC were similar; the t 1/2 and MRT values (over 2 h and close to 3 h, respectively, for both formulations) indicated the long circulating properties of the LNC carrier with a slow distribution and elimination phase. Survival curves of paclitaxel treated groups showed a statistical significant difference compared to the control survival curve ( P = 0.0036 and 0.0408). Animals treated with 4× 70 mg/m 2 of PX-LNC showed the most significant increase in mean survival times compared to the controls (IST mean 72%) and cases of long-term survivors were preferentially observed in the PX-LNC treated group (37.5%; 3/8). These results demonstrate the great interest to use LNC as drug delivery system for paclitaxel, permitting with an equivalent therapeutic efficiency to avoid the use of excipients such as polyoxyethylated castor oil for its formulation.

Pharmacokinetics and Amyloid Plaque Targeting Ability of a Novel Peptide-Based Magnetic Resonance Contrast Agent in Wild-Type and Alzheimer's Disease Transgenic Mice

A novel magnetic resonance (MR) imaging contrast agent based on a derivative of human amyloid beta (Abeta) peptide, Gd[N-4ab/Q-4ab]Abeta 30, was previously shown to cross the blood-brain barrier (BBB) and bind to amyloid plaques in Alzheimer's disease (AD) transgenic mouse (APP/PS1) brain. We now report extensive plasma and brain pharmacokinetics of this contrast agent in wild-type (WT) and in APP/PS1 mice along with a quantitative summary of various physiological factors that govern its efficacy. Upon i.v. bolus administration, (125)I-Gd[N-4ab/Q-4ab]Abeta 30 was rapidly eliminated from the plasma following a three-exponential disposition, which is saturable at higher concentrations. Nevertheless, the contrast agent exhibited rapid and nonsaturable absorption at the BBB. The brain pharmacokinetic profile of (125)I-Gd[N-4ab/Q-4ab]Abeta 30 showed a rapid absorption phase followed by a slower elimination phase. No significant differences were observed in the plasma or brain kinetics of WT and APP/PS1 animals. Emulsion autoradiography studies conducted on WT and APP/PS1 mouse brain after an i.v. bolus administration of (125)I-Gd[N-4ab/Q-4ab]Abeta 30 in vivo confirmed the brain pharmacokinetic data and also demonstrated the preferential localization of the contrast agent on the plaques for an extended period of time. These attributes of the contrast agent are extremely useful in providing an excellent signal/noise ratio during longer MR scans, which may be essential for obtaining a high resolution image. In conclusion, this study documents the successful plaque targeting of Gd[N-4ab/Q-4ab]Abeta 30 and provides crucial pharmacokinetic information to determine the dose, mode of administration, and scan times for future in vivo MR imaging of amyloid plaques in AD transgenic mice.

Pharmacokinetics and bioavailability of nimesulide in goats

The pharmacokinetic properties and bioavailability of cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug nimesulide were investigated in female goats following intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 4 mg/kg BW. Blood samples were collected by jugular venipuncture at predetermined times after drug administration. Plasma concentrations of nimesulide were determined by a validated high-performance liquid chromatography method. Plasma concentration-time data were subjected to compartmental analysis and pharmacokinetic parameters for nimesulide after i.v. and i.m. administration were calculated according to two- and one-compartment open models respectively. Following i.v. administration, a rapid distribution phase was followed by the slower elimination phase. The half-lives during the distribution phase (t1/2alpha) and terminal elimination phase (t1/2beta) were 0.11+/-0.10 and 7.99+/-2.23 h respectively. The steady-state volume of distribution (Vd(ss)), total body clearance (ClB) and mean residence time (MRT) of nimesulide were 0.64+/-0.13 L/kg, 0.06+/-0.02 L/h/kg and 11.72+/-3.42 h respectively. After i.m. administration, maximum plasma concentration (Cmax) of nimesulide was 2.83+/-1.11 microg/mL attained at 3.6+/-0.89 h (tmax). Plasma drug levels were detectable up to 72 h. Following i.m. injection, the t1/2beta and MRT of nimesulide were 1.63 and 1.73 times longer, respectively, than the i.v. administration. The bioavailability of nimesulide was 68.25% after i.m. administration at 4 mg/kg BW. These pharmacokinetic data suggest that nimesulide given intramuscularly may be useful in the treatment of inflammatory disease conditions in goats.

Absorption and Excretion of Luteolin and Apigenin in Rats after Oral Administration of Chrysanthemum morifolium Extract

Chrysanthemum morifolium extract (CME) has the protective effect on cardiovascular diseases. Luteolin and apigenin are two major bioactive components in vivo when CME is orally administrated to experimental animal. The present paper shows the study of the absorption and excretion of luteolin and apigenin in rats after a single oral dose of CME (200 mg/kg). The levels of luteolin and apigenin in plasma, urine, feces, and bile were measured by HPLC after deconjugation with hydrochloric acid or beta-glucuronidase/sulfatase. The results showed that the plasma concentrations of luteolin and apigenin reached the highest peak level at 1.1 and 3.9 h after dosing, respectively. The area under the concentration-time curves (AUC) for luteolin and apigenin were 23.03 and 237.6 microg h mL-1, respectively. The total recovery of the dose was 37.9% (6.6% in urine; 31.3% in feces) for luteolin and 45.2% (16.6% in urine; 28.6% in feces) for apigenin. The cumulative luteolin and apigenin excreted in the bile was 2.05% and 6.34% of the dose, respectively. All of the results suggest apigenin may be absorbed more efficiently than luteolin in CME in rats, and both luteolin and apigenin have a slow elimination phase, with a quick absorption, so a possible accumulation of the two flavonoids in the body can be hypothesized.

Pharmacokinetics of morphine in fish: Winter flounder ( Pseudopleuronectes americanus) and seawater-acclimated rainbow trout ( Oncorhynchus mykiss)

We made a single intraperitoneal (IP) injection of morphine sulfate (40 mg/kg) into winter flounder and seawater acclimated rainbow trout at 10°C and then followed its disposition by measuring the change in plasma morphine concentration for 100 h using a morphine specific ELISA. Disposition also was followed for 6 h after a single IV injection of 7.5 mg morphine sulfate in winter flounder. Plasma morphine reached a maximum within an hour post-injection IP and then decreased in a bi-exponential fashion with a rapid distribution phase followed by a slower elimination phase. The disposition was slower in flounder than in trout even though the fish were held at the same temperature. For example, plasma clearance was 76 mL h − 1 kg − 1 in the flounder but was almost twice as much in the trout (153 mL h − 1 kg − 1) and mean residence time was 27.9 h in the flounder but was 7.0 h in the trout. The present study is the first comprehensive pharmacokinetic analysis for any analgesic in an ectotherm, and our results show that: 1) significant intra-specific variation exists between fishes: and 2) the disposition of morphine in fish is approximately one order of magnitude slower than it is in mammals. These differences may be due in part to mass specific differences in cardiac output.

Pharmacokinetics of Telbivudine following Oral Administration of Escalating Single and Multiple Doses in Patients with Chronic Hepatitis B Virus Infection: Pharmacodynamic Implications

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.

PIMECROLIMUS: ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION IN HEALTHY VOLUNTEERS AFTER A SINGLE ORAL DOSE AND SUPPLEMENTARY INVESTIGATIONS IN VITRO

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.

A randomised, double blind, placebo controlled single ascending dose study of PYM50018, with an open label cross-over stage to assess food effect

Background and Aims PYM50018 has neuroprotective properties and an emerging safety profile that make it a promising candidate for the treatment of neurodegenerative disorders, such as amyotrophic lateral sclerosis. This study evaluated the pharmacokinetics, safety and tolerability of the compound, together with the effect of food on its bioavailability. Methods Forty healthy males 18 to 45 years who met the entry criteria were included. Four groups of ten subjects were randomly allocated to receive placebo (n=2) or PYM50018 (n=8; 80 mg, 240 mg, 480 mg or 960 mg). One group also received PYM50018 (240 mg) on two further occasions either after breakfast or fasted. Results Exposure to PYM50018 increased proportionately with dose. At higher exposures a second, slower elimination phase became apparent. Exposure to PYM50018 was increased after a high fat breakfast, as compared with the fasted state. There were no clinically significant changes in the safety parameters or adverse events. Conclusions PYM50018 is well tolerated by healthy male subjects as a single oral dose of up to 960 mg. Systemic exposure to oral PYM50018 is dose proportional. Food has a significant effect on the absorption kinetics of PYM50018. Clinical Pharmacology & Therapeutics (2005) 77, P67–P67; doi: 10.1016/j.clpt.2004.12.146

The disposition of enrofloxacin in seabream ( Sparus aurata L.) after single intravenous injection or from medicated feed administration

Serum concentrations of enrofloxacin (EF) after intravenous (i.v.) or oral administration of single doses (2.5 and 10 mg/kg b.w., respectively) were investigated in seabream ( Sparus aurata L.) kept in seawater at 25–27 °C. The tissue disposition of the drug was studied after oral administration. At prefixed time points, from 1 h to 5 days after administration, blood and edible tissues (muscle plus adherent skin) from 10 individuals in each group were collected and stored at −20 °C. Each serum and tissue sample was essayed for EF by HPLC after liquid–liquid extraction. Serum was also checked for the presence of the metabolite ciprofloxacin (CF). The quantification limits for EF were 0.010 μg/ml in serum and 0.015 μg/g in tissues. Following intravenous administration, considerably high serum concentrations of EF (range 2.605–3.810 μg/ml) were detected during the first 4 h. The concentrations decreased subsequently, indicating a first rapid distribution, followed by a slow phase of elimination. At the last time point of the experiment (120 h), there were still detectable amounts of EF in serum samples (range 0.040–0.087 μg/ml). Enrofloxacin levels of 0.335–1.138 μg/ml were reached in serum within 1 h after in feed administration. The maximum values were measured at 8 h (1.709–2.846 μg/ml), then slowly declined and were measurable (0.048–0.149 μg/ml) for up to 120 h. Compared to serum, lower concentrations of EF were determined in muscle plus skin: 0.156–0.398 μg/g after 1 h, 0.102–2.002 μg/g at 8 h and 0.015–0.031 μg/g at the last sample point. No CF was found in serum.

Comparative pharmacokinetics of coumarin anticoagulants L: Physiologic modeling of S-warfarin in rats and pharmacologic target-mediated warfarin disposition in man

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80–240h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man.

Comparative disposition kinetics and plasma protein binding of gentamicin sulphate in three juvenile animal species.

The pharmacokinetics of gentamicin was studied in lambs, calves and foals, respectively after single intravenous (i.v.) injections of 5 mg kg(-1) body weight. The plasma concentration-time curves of gentamicin sulphate were best fitted to follow a two-compartment open model in calves and foals and a three-compartment open model in lambs. Gentamicin showed high plasma level at 5 min post-injection. Then its concentration decreased gradually until its minimum detectable level at 10 and 12 h post-injection in foals and calves, respectively, was reached. In contrast, the plasma concentrations were much higher in lambs and persisted up to 48 h from the onset of injection. Values of pharmacokinetic parameters for gentamicin sulphate in different animals after i.v. injections were calculated. Pharmacokinetic data in lambs demonstrated a triphasic decline in plasma gentamicin concentration with slow terminal elimination phase (washout phase) with (t(1/2y)) of 7.7 h. Gentamicin showed a small volume of distribution Vd(ss) (80.3 ml kg(-1)) in lambs indicating that the drug is slightly distributed in extra-vascular tissues. The overall rate of total body clearance ClB in lambs was (0.46 ml kg(-1)) slower than in calves (1.5 ml kg(-1)) and foals (2.7 ml kg(-1)). In vitro protein binding per cent of gentamicin sulphate in plasma were 16.80, 11.03 and 7.98% in lambs, calves and foals. The results of this study emphasize the importance of determining the pharmacokinetics of gentamicin in each species of young animals separately.

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20 mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC 90 0.125 μg/mL) were lower than those of cefoperazone (MIC 90 0.5 μg/mL) although the latter was more effective against Escherichia coli strains (MIC 90 2.0 μg/mL vs. 4.0 μg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase ( t (1/2) λ2 84.0±21.3 min for cefoperazone and 81.4±9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1±13.5% and 35.9±5.4 μg/ mL ) were significantly higher than cefoperazone (41.4±7.1% and 24.5±3.0 μg/ mL ), but not the serum half-lives ( t 1/2el 134.3±12.6 min for cefoperazone and 145.4±12.3 min for cefamandole). The time above MIC 90 indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections ( T>MIC for S. intermedius 23.8±0.3 and for Staphylococcus aureus 21.6±0.6 h).