Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase inhibitor, BMS-188494, in healthy volunteers

A double-blind, placebo-controlled, parallel-group, ascending, multiple-dose study was completed in 45 healthy male volunteers to assess the maximum tolerated dose, pharmacokinetics, and pharmacodynamics of BMS-187745, a squalene synthase inhibitor, administered as multiple oral doses of its prodrug BMS-188494. Participants received a daily oral dose of 10 mg for 2 weeks, or a daily oral dose of 25, 50, 100, or 200 mg for 4 weeks. The absorption rate constant (ka) and bioavailability (F) values were estimated by fitting the plasma BMS-187745 concentration-time data to a biexponential function with a first-order ka. Values for F were similar for all five dose levels, and thus were independent of dose. The ka values also were similar for all dose groups except the 50-mg group, for which ka values were somewhat higher. The change in urinary excretion rate of farnesyl pyrophosphate metabolite (dioic acid) was determined to be a pharmacodynamic measure. There was no significant change in dioic acid excretion at doses of less than 100 mg given for 4 weeks. An indirect pharmacodynamic response model with threshold concentration (CT) and based on inhibition of squalene synthase was proposed to describe the effect versus time data. The pharmacodynamic data from all dose levels were fitted simultaneously to the proposed model and the fitted parameters estimated as CT = 3.9 micrograms/mL, kout = 0.47 hr-1, IC50 = 4.1 micrograms/mL, and Imax = 1.0. The proposed indirect response model requiring a threshold concentration provides a useful means of quantitating responses for a new type of therapeutic agent.     

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (F_srr and F_rr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of F_srr (13.67%) and F_rr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine. Received: 23 July 1998 / Final version: 2 February 1999     

Evaluation of a Targeted Prodrug Strategy to Enhance Oral Absorption of Poorly Water-Soluble Compounds

Purpose. The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound. Methods. Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose. Results. Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug. Conclusions. Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.     

Enhanced Oral Bioavailability of DDI After Administration of 6-Cl-ddP,an Adenosine Deaminase-Activated Prodrug,to Chronically Catheterized Rats

Purpose. 6-Cl-2,3-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself. Methods. Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC. Results. 6-Cl-ddP has poor apparent oral bioavailability (7% ± 3%, n = 3) but high bioavailability after portal administration (97% ± 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of >50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a > 10-fold increase in the oral bioavailability of ddI, from 3–7% to >50%, and a significant decrease in the variability in apparent bioavailability. Conclusions. These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.     

Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043)

BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.     

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.     

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies

Abstract

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone.     

Compartmental Absorption Modeling and Site of Absorption Studies to Determine Feasibility of an Extended-Release Formulation of an HIV-1 Attachment Inhibitor Phosphate Ester Prodrug

BMS-663068 is a phosphonooxymethyl ester prodrug under development for the treatment of HIV/AIDS. The prodrug is designed to overcome the solubility-limited bioavailability of the active moiety, BMS-626529. BMS-663068 is not absorbed from the gastrointestinal (GI) tract and requires enzymatic conversion by alkaline phosphatase to BMS-626529 immediately before absorption. In the light of the known short in vivo half-life of BMS-626529, compartmental absorption modeling was used to predict the potential feasibility of extended-release (ER) delivery to achieve target C_max:C_min ratios. To further refine the model with respect to colonic absorption, the regional absorption of BMS-626529 following delivery of BMS-663068 to upper and lower GI sites was characterized through a site of absorption study in human subjects. A refined model was subsequently applied to guide the development of ER tablet formulations. Comparisons of results from the refined model to the in vivo human pharmacokinetic data for three selected ER formulations demonstrate the utility of the model in predicting feasibility of ER delivery and in directing formulation development.     

Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin.

The aim of this study was to investigate the effect of quercetin on the bioavailability of paclitaxel after the oral administration of paclitaxel or a prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280 mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel pretreated with quercetin were increased significantly (P < 0.01 for paclitaxel; P < 0.05 for prodrug) compared to the control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of paclitaxel pretreated with quercetin were significantly higher (P < 0.01) than the control. The half-life (t(1/2)) and mean residence times were significantly (P < 0.05) longer compared to the control. The absolute bioavailability (AB%) of paclitaxel pretreated with quercetin was significantly higher (P < 0.01) than the control. The AUC of paclitaxel after administration of the prodrug to rats pretreated with quercetin was significantly (P < 0.05) higher than the prodrug control. The relative bioavailability of paclitaxel after administration of the prodrug to rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug control. The AB% of paclitaxel was increased significantly (P < 0.05) by quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel administered as a prodrug with or without pretreatment of quercetin was remarkably higher than the control. AUC, AB% and Cmax of paclitaxel after administration of the paclitaxel or prodrug pretreated with quercetin for 3 days were much higher than those administered after 20 min. It might have resulted from the physicochemical properties of the prodrug, which is a water-soluble compound and passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. It seems that the development of oral paclitaxel preparations as a prodrug or with quercetin is feasible, which is more convenient than the i.v. dosage forms.     

Prodrugs to Improve the Oral Bioavailability of a Diacidic Nonpeptide Angiotensin II Antagonist

DMP 811 is a diacidic angiotensin II antagonist. It has relatively low oral bioavailability in rats. A prodrug approach to improving oral bioavailability was tested. Five esters were synthesized and their stability in rat plasma in vitro was determined. The hydrolysis rates of these five esters ranged from almost immediate to negligible. A simple n-propyl ester was hydrolyzed very slowly (< 10% in 24 hr) in rat plasma in vitro, and after oral dosing in rats plasma prodrug concentrations were much greater than DMP 811 concentrations. A pivaloyloxymethyl ester (1) was hydrolyzed relatively rapidly in rat plasma in vitro. Prodrug 1 was rapidly hydrolyzed by the intestine in vitro, and the intestinal permeation of DMP 811 was increased. DMP 811 oral bioavailability was 47% in rats dosed with 10 mg/kg 1, compared to 11% for rats dosed with 10 mg/kg DMP 811. However, DMP 811 bioavailability was only 27% after a 2 mg/kg dose of 1. In vitro plasma hydrolysis of 1 was highly species-dependent, with a half-life of 13 hr in human plasma but only 1 min in rat plasma. The prodrug approach has potential for improving the oral bioavailability of DMP 811, but selection of the optimal prodrug must be done in humans or in a species, such as dogs, with hydrolysis characteristics closer to humans.     

Suramin as a Chemosensitizer: Oral Pharmacokinetics in Rats

Purpose. The purpose of this study was to determine if the 10-50 M plasma concentrations of suramin required to produce chemosensitization could be achieved by oral administration. Methods. Rats were given an oral dose of 100, 300, or 500 mg/kg unlabeled suramin by oral gavage. Rats receiving the 300 mg/kg oral dose of suramin also received a concomitant intravenous bolus injection of 50 Ci/kg of [³H]suramin, administered 57 min after the oral dose. The intravenous data were used to calculate the clearance. Serial plasma samples were collected over 24-336 h. Plasma concentration-time profiles were analyzed using noncompartmental and compartmental methods. The pharmacokinetic parameters derived for the 300 mg/kg oral and 50 Ci/kg intravenous doses were used to calculate the bioavailability and AUC at the three oral dose levels. Results. Plasma concentrations declined biexponentially following intravenous administration, with a distribution half-life of 2 h and an estimated terminal half-life of 276 h. Suramin absorption following oral gavage was variable and incomplete with mean maximal plasma concentrations of 9.04, 72.6, and 64.4 g/ml at doses of 100, 300, and 500 mg/kg, respectively. Seven of 15 rats exhibited two peak plasma concentrations at 1 h and 3 to 12 h, suggesting the existence of multiple absorption sites and/or enterohepatic circulation. Oral bioavailability, calculated using the clearance of the intravenous tracer dose, was <3% at all three dose levels. Conclusions. While plasma concentrations resulting from the 300 and 500 mg/kg oral doses of suramin were in the concentration range required to produce chemosensitization, the low bioavailability limits the usefulness of oral administration.     

In Vitro-In Vivo Evaluation of a Controlled Release Buccal Bioadhesive Device for Oral Drug Delivery

Purpose. To investigate the use of buccal bioadhesive device in targeting controlled drug delivery to the gastrointestinal tract. Methods. A three-leg crossover study was designed to evaluate the application of buccal bioadhesive device for providing controlled drug delivery to the gastrointestinal tract of a model drug cyanocobalamin in four healthy adult male beagle dogs. Results. In vitro dissolution studies using deionized water as the medium indicated that 100% of the drug was released within 15 min from a immediate release oral capsule formulation, whereas 90% of the drug was released within a period of 18 hrs from a buccal bioadhesive device formulation. Drug release from the buccal bioadhesive devices appeared to follow Higuchi's square root of time dependent model. The terminal half-life of the drug following I.V. administration in four dogs was found to be 16.4 ± 2.4 hrs. Following immediate release oral capsule administration of the drug C_max, t_max and bioavailability were 2333 ± 1469 ng/L, 2.5± 1.0 hrs and 14.1 ± 7.9%, respectively. Following buccal bioadhesive device administration of the drug C_max, t_max and bioavailability were 4154 ± 1096 ng/L, 11 ± 1.2 hrs and 35.8 ± 4.1%, respectively. Significantly higher bioavailability of the drug was observed with the buccal bioadhesive device administration when compared to the immediate release oral capsule. Conclusions. The buccal bioadhesive device appears to improve the oral bioavailability of cyanocobalamin by providing controlled delivery of the drug to the gastrointestinal tract.     

Disposition of radiolabeled BMS-204352 in rats and dogs

BMS-204352, a maxi-K channel opener, is currently under development for the treatment of stroke. The objective of this study was to determine the pharmacokinetics, mass balance and absolute oral bioavailability of [(14)C]-BMS-204352 in rats and dogs. [(14)C]-BMS-204352 was administered, to rats (n=10/group; parallel design, 6 mg/kg) and dogs (n=4/group; crossover design, 2 mg/kg), as an oral (PO) or as a 3-min intraarterial (IA) infusion in rats and a 6-min intravenous (i.v.) infusion in dogs. Blood, urine, and feces samples were collected and analyzed for unchanged BMS-204352 (plasma) using a validated LC/MS assay and for total radioactivity (plasma, urine, feces) using liquid scintillation counting. The mean total body clearance (CLT) and steady-state volume of distribution (VSS) values for the unchanged BMS-204352 were 2.58 +/- 0.48 l/h/kg and 6.3 +/- 1.14 l/kg, respectively, in rats and 0.21 +/- 0.02 l/h/kg and 4.06 +/- 0.47 l/kg, respectively, in dogs. In both species, the elimination half-life of total radioactivity was significantly longer as compared to the unchanged drug. After IA administration of radiolabeled BMS-204352 to rats, ca. 5.9 and 85% of radioactivity was recovered within 7 days in urine and feces, respectively; corresponding recoveries after PO dosing were 4.5 and 99.5%, respectively. The recoveries were similar in dogs, i.e., ca. 5.2 and 83% of administered radioactivity recovered in urine and feces, respectively, for IV dose and ca. 4 and 86%, respectively, for PO dose. These data indicate that nonrenal (biliary) elimination in both species was predominant. Based on comparable urinary recovery of radioactivity and plasma AUCs of radioactivity, the extent of oral absorption of BMS-204352 appeared to be complete in both species. The absolute oral bioavailability was 55% in rats and 79% in dogs. Bioavailability and extent of absorption data suggest evidence of first pass metabolism of BMS-204352 in the rat and dog.     

Potential Improvement in Shelf Life Using the Prodrug Approach. II. A Systematic Examination of Kinetic Requirements

The utilization time (UT) for a solution of a prodrug that is rapidly and completely converted to drug in the blood may be longer than the time for 10% loss of the initial concentration. The UT for an intravenous prodrug solution is the period during which the total prodrug and drug concentration exceeds 90% of the initial concentration. The influence of the rate of prodrug degradation (k _nc), its conversion (k _c) to drug, and the subsequent drug degradation (k _h) on the UT of a stored solution was examined by simulating the prodrug and drug concentration–time courses. The ratio of the shelf life of a prodrug solution to that of the parent drug (UT_ratio) was calculated using a wide range of values for the three rate constants. Three-dimensional plots relating the UT_ratio to the k _c, k _nc, and k _h values provide a basis for making a priori assessments of kinetic requirements for designing a prodrug to increase storage time. A parenteral prodrug intended to increase storage time may have a larger overall rate of loss than the parent drug, but it must have a smaller degradation rate (k _nc < k _h) to be successful. The UT for an oral prodrug solution depends upon the bioavailability of the prodrug relative to the drug in addition to the values for k_nc, k _c, and k _h. Two ampicillin prodrugs were used as models to calculate actual UT_ratio versus pH profiles. Intravenous solutions showed modest gains in the UT_ratio in the acid region, whereas oral solutions reached a UT_ratio as high as 22 by combining favorable rate constants with increased bioavailability. These actual UT_ratio versus pH profiles were interpreted in terms of the theory established using the simulations.     

Continuous Blood Withdrawal as a Rapid Screening Method for Determining Clearance and Oral Bioavailability in Rats

Purpose. To develop a methodology for continuous blood withdrawal in rats suitable for drug discovery screening purposes and perform limited validation studies with a series of test compounds. Methods. A reliable methodology for continuous blood withdrawal in rats was developed. The method is dependent on continuous heparin infusion during withdrawal and the minimization of constrictive, thrombogenic sites. Plasma drug concentrations from either intermittent sampling or continuous withdrawal experiments were determined with HPLC analysis. Results. The continuous withdrawal method was successfully adapted to rats such that blood samples could be reliably collected over a 6-hr experiment. The clearance and oral bioavailability values for theophylline, atenolol, propranolol, warfarin. BMS-182874 and BMS-A were determined from continuous withdrawal or intermittent sampling experiments. The results from the two methods were comparable, with each compound reliably placed in the same low, medium or high category based on clearance or oral bioavailability characteristics. Conclusions. The continuous withdrawal method proved to be a viable alternative to the classic intermittent sampling technique. The method should prove useful in drug discovery screening, where the evaluation of large numbers of compounds for systemic clearance or oral bioavailability is often necessary.     

Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa,a new prodrug of methyldopa

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.     

Dextran-Methylprednisolone Succinate as a Prodrug of Methylprednisolone: Local Immunosuppressive Effects in Liver After Systemic Administration to Rats

Purpose. The purpose of this work was to study the local immunosuppressive effects of systemically administered methylprednisolone (MP) and its prodrug, dextran-methylprednisolone (DMP), in rat livers. Methods. Single 5 mg/kg (MP equivalent) doses of MP or DMP were injected intravenously to rats, and livers were isolated at different time points (0-72 h; n = 4/time point). Isolated livers were stimulated ex vivo with bacterial lipopolysaccharide, and outlet perfusate and bile samples were analyzed for their concentrations of tumor necrosis factor (TNF)- by enzyme-linked immunosorbent assay. The area under the perfusate TNF- concentration-time curve (AUC) was used as a measure of immune response. Hepatic concentrations of MP and DMP were also measured by high-performance liquid chromatography. Results. Both MP and DMP resulted in a decrease in lipopolysaccharide-induced increase in TNF- AUC. MP injection 8 h before liver isolation resulted in a maximum of 50% decrease in TNF- AUC. Compared with MP, the maximum effect of the prodrug (DMP) was both more intense (80% reduction in TNF- AUC) and delayed (maximum inhibition at 24 h). Overall, the area under the effect (% inhibition of TNF-)-time (%inhibitionh) for DMP (3680 ± 406) was approximately four times more than that for the parent drug (846 ± 114). Whereas the MP concentrations in the liver were not quantifiable after the injection of the parent drug, relatively large concentrations of DMP and regenerated MP were found in the liver of DMP-injected rats. Conclusions. After systemic administration to rats, both MP and DMP exhibit local immunosuppressive effects in the liver. The local effects of the prodrug (DMP), however, appear to be more intense and sustained than those of the parent drug (MP).     

Development of cytarabine prodrugs and delivery systems for leukemia treatment

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin's lymphoma. The drug has a short plasma half-life, low stability and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in Phase III trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt, Pacira Pharmaceuticals Inc., New Jersey, USA) has been approved for the treatment of lymphomatous meningitis.

Areas covered in this review: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy.

What the reader will gain: This review provides in-depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provides insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability.

Take home message: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents.     

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N-phosphonooxymethyl prodrugs in rats and dogs.

N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.     

The site of reduction of sulphinpyrazone in the rabbit

1. Comparison of oral and i.v. administration of sulphinpyrazone (10 mg/kg) to rabbits showed that the oral route was associated with an incomplete bioavailability and a six-fold greater formation of the active sulphide metabolite.

2. The bile was an important route of elimination of unchanged sulphinpyrazone in rabbits (18% of an i.v. dose in four hours). Only small amounts of the sulphide appeared in the bile after i.v. administration.

3. Pretreatment with oral antibiotics decreased the area under the plasma concentration-time curve (AUC) for the sulphide but increased that of the parent drug. Excretion of the p-hydroxysulphide metabolite in urine was decreased 30-fold by antibiotic treatment.

4. The contents of the caecum showed the greatest capacity for sulphinpyrazone reduction in vitro. The liver possessed a slight ability to reduce sulphinpyrazone in vitro under anaerobic, but not aerobic, conditions.

5. The gut bacteria are the main site of reduction of sulphinpyrazone to the active sulphide metabolite in the rabbit.

6. These findings contrast with those obtained for sulindac which was reduced extensively under both aerobic and anaerobic conditions by rabbit-liver soluble fraction in vitro. The sulphide metabolites of both sulphinpyrazone and sulindac were oxidized to the parent drug by rabbit-liver microsomes.