Cyclodextrin-based nanosponges: effective nanocarrier for Tamoxifen delivery

The purpose of the present study was to develop Tamoxifen loaded β-cyclodextrin nanosponges for oral drug delivery. The three types of Tamoxifen loaded β-cyclodextrin nanosponges were synthesized by varying the molar ratios of β-cyclodextrin to carbonyldiimidazole as a crosslinker viz. 1:2, 1:4 and 1:8. The Tamoxifen nanosponge complex (TNC) with particle size of 400–600?nm was obtained by freeze drying method. Differential scanning calorimetry, Fourier transformed infra-red spectroscopy and X-ray powder diffraction studies confirmed the complexation of Tamoxifen with cyclodextrin nanosponge. AUC and C_max of TNC formulation (1236.4?±?16.12 µg·mL^?1 h, 421.156?±?0.91 µg/mL) after gastric intubation were 1.44 fold and 1.38 fold higher than plain drug (856.079?±?15.18 µg·mL^?1 h, 298.532?±?1.15 µg/mL). Cytotoxic studies on MCF-7 cells showed that TNC formulation was more cytotoxic than plain Tamoxifen after 24 and 48?h of incubation.     

Superior anti-neoplastic activities of triacontanol-PEG conjugate: synthesis,characterization and biological evaluations

Triacontanol (TA, C₃₀H₆₂O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis-inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-κB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti-malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25?ng·mL^?1·h^?1_, p?p?p??1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Effect of quinidine on the intestinal secretion of digoxin in guinea pigs

Following i.v. injection of digoxin (10 μg kg^?1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearily with time. After 3 h, L/P was 8·7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg^?1 p.o., 2h before experiment) both the L/P ratio (5·7; p < 0·01) and the digoxin content of jejunal tissue (– 32 per cent; p < 0·01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.     

Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent,and indomethacin after oral administrations in rats

Abstract— N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M₁) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M₁ and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C_max (1·13 μg mL^?1) of M₁ after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C_max (3·38 μg mL^?1) after 3 h in plasma. The mean AUC of M₁ and indomethacin in plasma were 5·45 μg h mL^?1 and 22·49 μg h mL^?1, respectively. The mean t_max, C_max and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/10⁸ cells and 58·6 ng (164 pmol) h/10⁸ cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/10⁸ cells and 95·2 ng (266 pmol) h/10⁸ cells, respectively. The PMNs/plasma ratio of M₁ was about 2·8 times that of indomethacin. These results indicate that the association of M₁, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.     

Thermosensitive PEG–PCL–PEG (PECE) hydrogel as an in situ gelling system for ocular drug delivery of diclofenac sodium

Development of efficient ocular drug delivery systems was still a challenging task. The objective of this article was to develop a thermosensitive PEG–PCL–PEG (PECE) hydrogel and investigate its potential application for ocular drug delivery of diclofenac sodium (DIC). PECE block polymers were synthesized by coupling MPEG-PCL co-polymer using IPDI reagent, and then its sol–gel transition as a function with temperature was investigated by a rheometer. The results showed that 30% (w/v) PECE aqueous solution exhibited sol–gel transition at approximately 35?°C. In vitro release profiles showed the entrapped DIC was sustained release from PECE hydrogels up to 7 days and the initial drug loading greatly effect on release behavior of DIC from PECE hydrogels. MTT assay results indicated that no matter PECE or 0.1% (w/v) DIC-loaded PECE hydrogels were nontoxic to HCEC and L929 cells after 24?h culturing. In vivo eye irritation test showed that the instillation of either 30% (w/v) PECE hydrogels or 0.1% (w/v) DIC-loaded PECE hydrogels to rabbit eye did not result in eye irritation within 72?h. In vivo results showed that the AUC_0–48?h of 0.1% (w/v) DIC-loaded PECE hydrogels exhibited 1.6-fold increment as compared with that of commercial 0.1% (w/v) DIC eye drops, suggesting the better ophthalmic bioavailability could be obtained by the instillation of 0.1% (w/v) DIC-loaded PECE hydrogels.     

Incorporation of rosuvastatin-loaded chitosan/chondroitin sulfate nanoparticles into a thermosensitive hydrogel for bone tissue engineering: preparation,characterization, and cellular behavior

Rosuvastatin (RSV) has been shown to have significant impact on the simulation of bone regeneration after local injection. The current study aimed to develop a localized controlled delivery system from RSV by incorporating RSV-loaded chitosan/chondroitin sulfate (CTS/CS) nanoparticles into thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel. RSV-loaded CTS/CS nanoparticles were prepared by ionic gelation, and the impact of various formulation variables was assessed using the Box–Behnken design. Consequently, optimized RSV-loaded nanoparticles were incorporated into the PF127/HA hydrogel. Rheological properties, degradation rates of hydrogels, and the release rate of RSV from hydrogel were examined. Mean particle size, zeta potential, entrapment efficiency, and mean release time of the optimized RSV-loaded nanoparticles were confirmed as 283.2?±?16?nm, –31.2?±?6.8?mV, 63.1?±?4.2%, and 6.14?±?0.3?h, respectively. The hydrogel containing 3% w/v CTS/CS nanoparticles existed as a solution with low viscosity at room temperature converted to a semisolid upon increasing the temperature to 35?°C. Hydrogel engrafted with CTS/CS showed controlled release of RSV during 48?h with superior in vitro gel stability. As revealed by cytotoxicity and mineralization assays, incorporation of RSV-loaded particles into PF127/HA hydrogel led to improvement in osteoblast viability and proliferation.     

Pharmacokinetic and Pharmacodynamic Studies of the Histamine H1-Receptor Antagonist Ebastine in Dogs

Abstract— The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0·01 mL of a 0·2 mg mL^?1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4·38 ± 1·01 h after 10 mg ebastine and 4·09 ± 0·74 h after 20 mg ebastine; the distribution volume was 3·99 ± 0·88 and 3·65 ± 0·75 L kg^?1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0·67 ± 0·24 L h^?1 kg^?1 and after 20 mg ebastine was 0·63 ± 0·17 L h^?1 kg^?1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0·001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3–4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0·17 and 0·22 h^?1 after 10 and 20 mg ebastine with a half-life of 4·13 and 3·56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18·9 ± 4.8 ng mL^?1 after 10 mg and 18·2 ± 5.7 ng mL^?1 after 20 mg ebastine.     

Analgesic activity of Eugenia jambolana leave constituent: A dikaempferol rhamnopyranoside from ethyl acetate soluble fraction

Context: Eugenia jambolana Lam. (Myrtaceae) is a medicinal plant used in folk medicine for the treatment of diabetes, inflammation, and pain.

Objective: We investigated the antinociceptive effect of kaempferol-7-O-α-l-rhamnopyranoside]- 4′-O-4′-[kaempferol-7-O-α-l-rhamnopyranoside (EJ-01), isolated from the E. jambolana leaves.

Materials and methods: EJ-01 (3, 10, and 30?mg?kg^?1, orally) was assessed for peripheral (formalin-nociception and acetic acid-writhing) and central (hot plate and tail flick test) analgesic activity in mice and the in vitro anti-inflammatory activity (25, 50, and 100?µg?mL^?1) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells.

Results and discussion: EJ-01 (10 and 30?mg?kg^?1) significantly inhibited mean writhing counts (37.74 and 36.83) in acetic acid writhing and paw licking time (55.16 and 45.66?s) in the late phase of the formalin test as compared with the respective control (60.66 and 104.33?s). EJ-01 did not show analgesic activity in central pain models. Significant reduction in the tumor necrosis factor (TNF)-α (295.48, 51.20, and 49.47?pg?mL^?1) and interleukin (IL)-1β (59.38, 20.08, and 15.46?pg?mL^?1) levels were observed in EJ-01-treated medium (25, 50, and 100?µg?mL^?1) as compared with vehicle-treated control values (788.67 and 161.77?pg?mL^?1), respectively. Significant reduction in total nitrite plus nitrate (NO_x) levels (70.80?nmol) was observed in the EJ-01-treated medium (100?µg?mL^?1) as compared with the vehicle-treated value (110.41?nmol).

Conclusion: EJ-01 is a valuable analgesic constituent of E. jambolana leaves and this study supports the pharmacological basis for the use of this plant in traditional medicine for curing inflammatory pain.     

Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir

Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7?±?2.0%, 41.8?±?1.9%, and 45.3?±?2.2%; drug loadings 3.87?±?0.20%, 2.79?±?0.13% and 3.02?±?0.15%; yield 85.2?±?3.0%, 86.9?±?4.6% and 76.9?±?2.1%; particle sizes 116.6?±?4.5, 143.0?±?3.8 and 134.1?±?5.2?nm; and zeta potential ?15.0?±?4.96, ?13.8?±?5.26 and ?13.9?±?5.14?mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.     

Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice

Abstract

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitive in situ hydrogel, consisting of chitosan (CS) and β-glycerophosphate (β-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol–gel temperature, flow behavior and viscosity of these CS/β-GP systems. The optimized formulation exhibited sol–gel transition at 40.2?±?0.4?°C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/β-GP hydrogel in phosphate buffer saline (pH?=?7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50?h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/β-GP hydrogel, was higher than that of TPT in saline and TPT in CS/β-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/β-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs.     

Montelukast prevents vascular endothelial dysfunction from internal combustion exhaust inhalation during exercise

Associations between high particulate matter (PM) pollution and increased morbidity and mortality from coronary heart disease have been identified. This study assessed leukotriene (LT) participation in PM-induced vascular endothelial dysfunction. Ten healthy males exercised 4 times for 30?min in both high PM (550,286?±?42,004 particles·cm^?3) and low PM (4571?±?1922 particles·cm^?3) after ingesting placebo (PL) or 10?mg montelukast (MK; half-life 3–6?h), a leukotriene receptor antagonist. Brachial artery flow-mediated dilation (FMD) was measured pre- and 30?min, 4?h, 24?h post-exercise. No basal brachial artery vascoconstriction was evident from high PM exercise. High PM blunted FMD, whereas high PM MK, low PM PL, and low PM MK demonstrated normal FMD (p < .003). Change in FMD (pre- to post-exercise) for high PM PL was different than for high PM MK, low PM PL, and low PM MK at 30?min post-exercise (p?<?.007). At 4?h, high PM MK FMD blunting increased (p?=?.1). At 24?h, high PM FMD blunting persisted (p?<?.05); no difference was observed between high PM PL or MK treatment, but was different that low PM PL/MK treatments (p?<?.05). MK blocked high PM post-exercise FMD blunting and maintained normal response, suggesting that leukotrienes are involved in PM-initiated vascular endothelial dysfunction.     

In-vivo anti-tumor activity of a novel poloxamer-based thermosensitive in situ gel for sustained delivery of norcantharidin

In order to develop a novel norcantharidin (NCTD) delivery system with slow drug release and specific targeting characteristics, we have developed a Poloxamer-based NCTD thermosensitive in situ gel. The evaluation of the characteristics of this system using both in vitro and in vivo methods was previously reported. However, its anti-tumor activity in vivo is still not confirmed. Thus, the potential anti-tumor activity and relative mechanism were investigated in a murine H22 hepatoma model. Tumor-bearing mice were treated with different dose of NCTD thermosensitive in situ gel (3.3?mg/kg, 6.6?mg/kg, and 9.9?mg/kg, respectively by intra-tumor injection once every three days, totaling 5 injections per group. Control groups included untreated or NCTD injection (2.2?mg/kg, qd) or blank in situ gel. The expression of vascular endothelial growth factor (VEGF) and CD44 in tumor tissue was examined by immunohistochemistry (IHC) staining. Treatment with middle or high dose of NCTD thermosensitive in situ gel significantly induced tumor regression, inhibited VEGF and CD44 expression and improved survival of tumor-bearing mice. The efficacy of NCTD thermosensitive in situ gel is higher than that of free NCTD injection. Therefore, NCTD thermosensitive in situ gel is a novel NCTD delivery approach for chemotherapeutic treatment of cancer.     

Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration

Abstract— The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0·5 h) were 2341±540 (day 0), 1956 ± 325 (day 7) and 2908 ± 1369 ng mL^?1 (day 28). Corresponding AUC values of 1742 ± 488, 1583 ± 422 and 2683 ± 1249 ng mL^?1 h were found. MRT increased significantly from 0·46 ± 0·06 h on day 0 to 0·67 ± 0·02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 ± 285, 685 ± 171 and 887 ± 264 ng g^?1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.     

Stability and pharmacokinetic studies of a new immunosuppressant,mycophenolate mofetil (RS-61443), in rats

Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non-enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg^?1, the terminal elimination half-life,-t_1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL^?1. After intraduodenal (ID) administration of MPM at 16.7 mg kg^?1, t_1/2β was 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL^?1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a new oral immunosuppressant.     

Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease

A microsphere–gel in situ forming implant (MS–Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson’s disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM–MS prepared by a modified emulsion-phase separation method and optimized by Box–Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of in vitro drug release (60?days). An in vivo pharmacokinetic study indicated a significant reduction (p?in situ gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (p?p?in situ phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs.     

A LIMITED SAMPLING METHOD FOR THE ESTIMATION OF FLUNARIZINE AREA UNDER THE CURVE (AUC) AND MAXIMUM PLASMA CONCENTRATION (CMAX)

A limited sampling model has been developed for flunarizine following a 30 mg oral dose in epileptic patients who were receiving phenytoin or carbamazepine or both, to estimate the area under the curve (AUC) and maximum plasma concentration (C_max). The model was developed using training data sets from 30, 20, 15, or 10 patients at one or two time points. The equations describing the models for AUC using two time points (3 and 24 h) and C_max for the training data set of 30 subjects were AUC_predicted=11·1 C_{3 h}+121·4 C_{24 h}–157 (r =0·80) C_{max(predicted)}=0·036 AUC+42·9 (r =0·74) The model was validated on 64 patients who received flunarizine orally. The model provided reasonably good estimates for both AUC and C_max. The mean predicted AUC of flunarizine was 1230±717 ng h mL⁻¹, whereas the observed AUC was 1203±900 ng h mL⁻¹. The bias of the prediction was 2% and precision was 28%. The mean predicted C_max of flunarizine was 86±32 ng mL⁻¹ as compared to an observed mean C_max of 90±42 ng mL⁻¹. The bias and precision of the prediction were 4% and 24%, respectively. The method described here may be used to estimate AUC and C_max for flunarizine without detailed pharmacokinetic studies. © 1997 by John Wiley & Sons, Ltd.     

Pharmacokinetics of Chlorimipramine,Chlorpromazine and their N-Dealkylated Metabolites in Plasma of Healthy Volunteers After a Single Oral Dose of the Parent Compounds

Abstract— A single oral dose of 0·7 mg kg^?1 clorimipramine (n= 18) and chlorpromazine (n= 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC _0–24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 ± 87 and 124 ± 14 ng mL^?1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43·8 ng mL^?1, an average of 3·4 h after dosage, whereas the mean peak chlorpromazine level was 15·1 ng mL^?1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.     

Pharmacokinetics of the antiarrhythmic agent tiracizine: Steady state kinetics in comparison with single-dose kinetics

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, C_max,ss = 391.8 ng mL^?1 against C_max,sd = 132.8 ng mL^?1; M2, C_max,ss = 143.2 ng mL^?1 against C_max,sd = 25.8 ng mL^?1). However, significant increases of AUC (AUCτ = 261.9 ng h mL^?1 against AUC_0–∞,sd = 182.9 ng h mL^?1), C_max (C_max,ss = 75.9 ng mL^?1 against C_max,sd = 56.9 ng mL^?1) and t_1/2β (t_1/2β,ss = 4.0 h against t_1/2β,sd = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the t_max of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.     

间尼索地平控释微丸Beagle犬体内药动学研究

目的建立间尼索地平血药浓度的高效液相色谱-质谱联用方法,研究Beagle犬单剂量口服间尼索地平控释微丸的药动学。方法用HPLC-MS法测定健康Beagle犬单剂量口服间尼索地平控释微丸和普通微丸的血药浓度,以DAS 2.0软件计算药动学参数。结果单剂量给药后,控释微丸和普通微丸的tmax分别为(11.154±0.5077)h和(2.213±0.3225)h,Cmax分别为(79.40±10.60)ng.mL1和(116.7±20.35)ng.mL1,AUC分别为(1227.8±296.0)ng.h.mL1和(867.8±146.7)ng.h.mL1,控释微丸的相对生物利用度为141.5%。结论本方法准确、灵敏,间尼索地平控释微丸血药浓度平稳,可较长时间保持血药浓度。