Oral Administration In Beagle Dogs Research Articles

Hydrochlorothiazide/Losartan Potassium Tablet Prepared by Direct Compression.

Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53–26.91%), microcrystalline cellulose (MCC PH102, 32.86–43.31%), pre-gelatinized starch (Starch-1500, 10.96–15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150–300 MPa) and tableting speed (1200–2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression.

Enhanced Oral Bioavailability of Felodipine from Solid Lipid Nanoparticles Prepared Through Effervescent Dispersion Technique.

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.

Pharmacokinetic analysis of mosapride following intravenous and oral administration in beagle dogs.

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1mg single administration of mosapride) and oral (5mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography-tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14±1.14hr-1 and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.

Fipronil Tablets: Development and Pharmacokinetic Profile in Beagle Dogs.

Increased human-pet interactions have led to concerns related to the prevention and treatment of ectoparasite infestations. Fipronil (FIP) is a widely used ectoparasiticide in veterinary medicine available for topical administration; however, its use may cause damage to the owners and the environment. The aim of the study was to develop immediate-release tablets of FIP, as well as to determine its pharmacokinetic properties after oral administration in beagle dogs. The prepared FIP tablets were evaluated for pre-compression (angle of repose, speed flow, and Carr's index) and post-compression (weight variation, friability, thickness, hardness, disintegration time, and dissolution rate) parameters. Orally administered FIP at a dose of 2mg/kg was rapidly absorbed with Cmáx of 3.13 ± 1.39μg/mL at 1.83 ± 0.40h post treatment (P.T.) and metabolized with 1.27 ± 1.04μg/mL at 2.33 ± 0.82h P.T. for fipronil sulfone (SULF) (the primary metabolite). The elimination of FIP and SULF occurred slowly and had maintained quantifiable plasma levels in the blood for up to 28days P.T. The goal of the study is aligned with the concept of One Health, which aims to collaboratively achieve the best health for people, animals, and the environment. Therefore, the use of FIP tablets for the control of ectoparasites in dogs may be a safer alternative for owners and the environment.

Development of a gastroretentive delivery system for acyclovir by 3D printing technology and its in vivo pharmacokinetic evaluation in Beagle dogs.

Gastroretentive (GR) systems are designed to prolong gastric residence time to allow sustained absorption and improve the oral bioavailability of drugs with a narrow absorption window in the upper part of the gastrointestinal tract. The present study aimed to develop a GR system for acyclovir using 3D printing technology and evaluate its in vivo pharmacokinetics after oral administration in Beagle dogs. The system consisted of a gastro-floating device, which can float in the gastric fluid, prepared by a fused deposition modeling 3D printer and conventional acyclovir sustained-release (SR) tablet. The acyclovir SR tablet was inserted to the floating device to allow sustained release of the drug in the stomach. The buoyancy and sustained-release property of the developed GR system were determined using an in vitro dissolution test, in vivo pharmacokinetic study, and abdominal X-ray imaging in Beagle dogs. The in vivo dissolution profiles of the GR system were also predicted based on the in vivo pharmacokinetic data using a population pharmacokinetic (POP-PK) model. In the dissolution test, the sustained-release characteristic of the GR system was identified with a time corresponding to 80% dissolution (T80) of 2.52 h. Following oral administration of the GR system, the time to reach the maximum concentration (Tmax) of acyclovir was significantly prolonged, whereas the maximum concentration (Cmax) decreased and the area under the curve increased compared with those obtained after the administration of immediate-release and SR tablets, indicating prolonged absorption. By X-ray imaging, we showed that the developed GR system stayed in the stomach for more than 12 h. The POP-PK model successfully described the observed plasma concentration-time data and predicted the in vivo biphasic dissolution profiles of the GR system, which was significantly different from the in vitro dissolution. The developed GR system could be applied to various drugs and had great prospects in the design and development of novel controlled-release formulations.

Formulation of a film-coated dutasteride tablet bioequivalent to a soft gelatin capsule (Avodart®): Effect of γ-cyclodextrin and solubilizers

The aim of this study was to optimize a tablet formulation of dutasteride that is bioequivalent to a commercially available soft gelatin capsule (Avodart®). The effect of cyclodextrin on enhancing the aqueous solubility of dutasteride was investigated, after which the formulation was further optimized with solubilizing polymer and surfactant. Among the cyclodextrins tested, the highest solubility was observed when dutasteride was complexed with γ-cyclodextrin. Moreover, the addition of polyvinylpyrrolidone and Gelucire/TPGS further enhanced the solubility of dutasteride. Differential scanning calorimetry (DSC) and powder X-ray diffraction (pXRD) studies demonstrated that dutasteride existed in the amorphous form in the complex. Optimized dutasteride complexes were selected after a pharmacokinetic study in rats, and film-coated tablets were prepared by the direct compression method. In vitro dissolution profiles for the tablets of dutasteride complexes were similar to those of the reference. Moreover, pharmacokinetic parameters including the Cmax and AUC values after oral administration in beagle dogs were not significantly different from those of the reference with a relative bioavailability of 92.4%. These results suggest the feasibility of developing a tablet formulation of dutasteride using cyclodextrin complex in addition to a solubilizing polymer and surfactant.

Determination of a astragaloside IV derivative LS-102 in plasma by ultra-performance liquid chromatography-tandem mass spectrometry in dog plasma and its application in a pharmacokinetic study

BackgroundAstragalosidic acid (LS-102) is a new water-soluble derivative of astragaloside IV - a major effective component isolated from the Chinese herb Astragali Radix. Our previous study showed that LS-102 exhibited potent cardiovascular activity. PurposeThe objective of this study was to investigate the pharmacokinetic properties of LS-102 after single-dose, oral administration in beagle dogs by developing and validating an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Method and resultThe chromatographic separation was performed on a Acquity HSS C18 column (100 mm × 2.1 mm, 1.8 µm) by a gradient elution using a mobile phase consisting of water and acetonitrile at a flow rate of 0.35 ml/min. The analytes were detected with a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode. Method validation revealed a wide linearity over the range of 2.0–10,000 ng/ml together with satisfactory intra- and inter-day precision, accuracy, and recovery. Stability testing showed that LS-102 spiked into dog plasma was stable for 4 h at room temperature, for up to 2 weeks at −80 °C, and during three freeze-thaw cycles. The method was effectively and successfully applied to the pharmacokinetics of LS-102 after oral administration (5, 10 and 20 mg/kg) to beagle dogs. Peak plasma concentrations are attained within approximately 2 h after oral administration with a half-life ranging from 1.55 h to 4.49 h. The plasma concentration-time curve of LS-102 after oral administration presents the phenomenon of a double-peak absorption phase. The peak concentration and area under the concentration-time curve of LS-102 seemed to increase with the increasing doses proportionally, that suggesting linear pharmacokinetics in dogs. Meanwhile, the doxorubicin (Dox)-injured H9c2 cell model was prepared by incubating the cells in 1 µM Dox for 24 h. MTT assay and LDH release measurement showed that LS-102 protected against Dox-induced cardiomyocyte death. ConclusionThe obtained results may help to guide the further pre-clinical research of LS-102 as a potentially novel cardioprotective agent.

Application of Carrier and Plasticizer to Improve the Dissolution and Bioavailability of Poorly Water-Soluble Baicalein by Hot Melt Extrusion

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.

Pharmacokinetic Interaction Between Polyphyllin II and Hyperoside Extracts of Rhizoma Paridis and Hypericum Perforatum After Oral Administration in Beagle Dogs

Pharmacokinetic Interaction Between Polyphyllin II and Hyperoside Extracts of Rhizoma Paridis and Hypericum Perforatum After Oral Administration in Beagle Dogs

Toxicokinetics of naringin and its metabolite naringenin after 180-day repeated oral administration in beagle dogs assayed by a rapid resolution liquid chromatography/tandem mass spectrometric method

Toxicokinetic characteristics of naringin and its metabolite naringenin were investigated in beagle dogs after oral administration of naringin at the doses of 20, 100, or 500 mg/kg/day in a repeated-dose study for 1, 30, 90, and 180 days. Plasma concentrations of naringin and naringenin were determined by a rapid resolution liquid chromatography/electrospray ionization/tandem mass spectrometric method. The results showed that no differences in systemic exposure were observed between male and female beagle dogs. Systematic exposure exhibited dose-dependent increase for both naringin and naringenin. No significant accumulations were observed. Results would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.

Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals

In this paper work, four naked nanocrystals (size range 80–700 nm) were prepared without any surfactant or polymer using the solvent/nonsolvent method. The effects of particle size on their solubility, dissolution, and oral bioavailability were investigated. Solubility and dissolution testing were performed in three types of dissolution medium, and the studies demonstrated that the equilibrium solubilities of coenzyme Q10 nanocrystals and bulk drugs were not affected by the dissolution media but the kinetic solubilities were. Kinetic solubility curves and changes in particle size distribution were determined and well explained by the proposed solubilization model for the nanocrystals and bulk drugs. The particle size effect on dissolution was clearly influenced by the diffusion coefficients of the various dissolution media, and the dissolution velocity of coenzyme Q10 increased as particle size decreased. The bioavailability of coenzyme Q10 after oral administration in beagle dogs was improved by reducing the particle size. For 700 nm nanocrystals, the AUC0–48 was 4.4-fold greater than that for the coarse suspensions, but a further decrease in particle size from 700 nm to 120 nm did not contribute to improvement in bioavailability until the particle size was reduced to 80 nm, when bioavailability was increased by 7.3-fold.

An ultra-high sensitive bioanalytical method for plasma melatonin by liquid chromatography–tandem mass spectrometry using water as calibration matrix

For the endogenous substances with an ultra-low level in biological fluids, such as melatonin, the blank biological matrix is obviously not “blank”. This problem leads to a serious issue of the bioanalytical methods development and validation by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). This work developed and validated an ultra-high sensitive bioanalytical method for plasma melatonin by LC–MS/MS using water as calibration matrix. The lower limit of quantitation of the method was verified to be 1.0 pg/mL and the method exhibited a linear range of 1–5000 pg/mL. Potential matrix effects, accuracy and precision were fully monitored and validated by two complementary quality control approaches respectively using water and the pooled plasma as matrix. The intra-run and inter-run precisions were less than 11.5% and 12.2%, respectively, and the relative error was below ±13.8% for all of 5 quality control levels. The method was successfully applied to investigate the daytime (8:00 AM–8:00 PM) baseline level of endogenous plasma melatonin, as well as the pharmacokinetic profiles of exogenous melatonin after oral administration in beagle dogs.

비글견을 이용한 케토롤락트로메타민 서방형 펠렛 제제의 위궤양 증상 비교와 약물속도론적 평가

Ketrorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug (NSAID) is required repeated administration due to its short blood half-life. To avoid dose-dependent side effects of KT, sustained-release pellets containing KT were prepared by coating with Eudragit RS 100 and Eudragit NE 30D. The in vitro and in vivo drug release behavior of KT from Eudragit RS 100 and NE 30D coated pellet (SR-A), Eudragit RS 100 coated pellet (SR-B) and conventional commercial immediate-release tablet (IR) was investigated. KT from SR-A and SR-B was slowly released over several hours, whereas IR showed rapid initial release in vitro. The pharmacokinetic study in vivo was performed by oral administration in beagle dogs. 5 mg IR was administered 3 times at intervals 5 hr. Five milligrams of IR was administered 3 times at intervals of 5 hr and 15 mg of SR-A and SR-B did once. After administering IR, KT concentration in blood showed high peak- trough fluctuation and stomach ulcer were discovered. On the other hand, SR-A and SR-B sustainedly released KT and reduced the occurrence of stomach ulcer. There sustained-release pellets will be effective system to minimize dosedependent of side effect and improve patient compliance.

Design and Evaluation of pH-Independent Pulsatile Release Pellets Containing Isosorbide-5-mononitrate

A three-layered, pH-independent pulsatile release pellets system containing isosorbide-5-mononitrate (ISMN) was studied. The process of the heart disease such as angina has a close relationship to the chronobiology, which gives rise to the need of a pulsatile drug deliver system for the anti-anginal drug. In this study, pellets containing ISMN were firstly prepared as the core, and then layered with a swelling layer followed by an water-insoluble control layer. The core pellets were formulated with microcrystalline cellulose (MCC) and lactose, and were prepared by extrusion-spheronization. The preparation was optimized by Box-Behnken experimental design, when taking the MCC/lactose ratio as swell as the operating conditions of extrusion-spheronization as variables. The experimental results demonstrated the relationships between formulation, operation and properties of the product, and meanwhile provided optimized values for the parameters. The core pellets were coated by a fluidized bed coater, and pellets with various coating types and coating levels were studied by in vitro dissolution tests. The effects of both swelling layer and control layer on the lag time and the drug release time were studied, in order to predetermine the lag time and release time. The pellets were also evaluated in vivo by studying the pharmacokinetics after oral administration in beagle dogs. The pellets achieved a lag time of 4.1 h in vivo, which had a good consistency with the in vitro results, and the relative bioavailability was nearly 100% comparing to the normal tablets.

Pharmacokinetics of Huperzine A after transdermal and oral administration in beagle dogs

Comparison of single and multiple dose pharmacokinetics between patches and conventional tablets of Huperzine A (Hup-A) was performed in beagle dogs to evaluate the patches’ controlled drug release characteristics in vivo, a newly developed transdermal system for treatment of Alzheimer disease. Results showed that transdermal administration of Hup-A prolonged T max value (24 h vs. 3 h, P < 0.01), lowered C max value (3.4 ± 0.2 ng mL −1 vs. 9.8 ± 1.0 ng mL −1, P < 0.01), and produced a relatively constant serum concentration within 84 h after a single transdermal dose of 4 mg/20 cm 2 Hup-A patches. Following application of the patches, Hup-A serum concentrations increased for approximately 12–24 h, reaching an average C max of 3.4 ± 0.2 ng mL −1. Thereafter, a serum concentration of at least 2.1 ng mL −1 was maintained for up to 84 h. The serum concentration was maintained within the range of 2.4–4.3 ng mL −1 during 2-week wearing period after multiple dosing, and the degree of fluctuation at the steady state of td and po administration was significantly different (0.51 vs. 1.99, P < 0.01). This study indicates that Hup-A patches exhibited good controlled-release properties in vivo, maintained a relatively constant serum concentration within 3.5 d after wearing, and are suitable for twice-weekly application.

Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs

In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.

Fast-disintegration oral tablets having sustained release property

Fast-disintegrating (FD) tablets containing nicorandil-loaded dry emulsions were prepared and their controlled-release properties were examined and compared with the plain FD tablets (FD tablets without dry emulsions) and commercial tablets. The dry emulsions were prepared with myristyl alcohol and stearyl alcohol and their property was modified by mixing the ratio of the two alcohols. Disintegration time of the prepared FD tablets was sufficiently fast (i.e., 12 to 23 s). In vitro release of nicorandil from the FD tablets containing the dry emulsions was sustained over 6 h, while that from plain FD and commercial tablets was complete within 5 min. In vivo absorption of nicorandil from the tablets was evaluated by oral administration in beagle dogs. FD tablets containing dry emulsions showed a similar AUC, lower Cmax, and delayed Tmax compared to the plain FD and commercial tablets. These results suggest that the dry emulsion-loaded FD tablets can be utilized to improve the sustained-release property of active drugs.

Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs.

Fifty-six adult beagle dogs (28 male, 28 female) were orally administered thalidomide at 43, 200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose group) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 26 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/group; high-dose and control groups) were dosed for 53 weeks, euthanized, and necropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidomide administration were green-colored urine, white-colored fecal residue presumed to be unchanged thalidomide, enlarged and/or blue coloration of female mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmoscopy, neurological function, and endocrine function. The mostly slight and/or transient variations observed in some hematology and blood chemistry values of dosed dogs were considered to be toxicologically insignificant and were supported by the lack of histopathologic correlates. The only gross finding attributable to thalidomide was a yellow-green discoloration of the femur, rib, and/or calvarium that was observed at each euthanization interval including recovery. There was no microscopic correlate for this finding. No thalidomide-related microscopic changes were seen in any of the organs and tissues at 26 weeks. Mammary duct dilatation and/or glandular hyperplasia observed in females at 53 and 58 weeks and hepatic bile pigment exhibited by high-dose males at 53 weeks were microscopic changes considered to be thalidomide-related. There was no gross and histopathologic evidence of any tumors. In summary, thalidomide at up to 1000 mg/kg/day for 53 weeks did not induce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/kg/day.

In Vivo Evaluation of Zidovudine (AZT)-Loaded Ethylcellulose Microspheres After Oral Administration in Beagle Dogs

The purpose of this study was to evaluate the in vivo performance of sustained-release zidovudine (AZT) microspheres after oral administration in Beagle dogs, and to establish an in vitro–in vivo correlation. Two AZT microsphere formulations as well as AZT powder were administered to four Beagle dogs. Plasma samples were analyzed by HPLC. The plasma concentration–time data was analyzed by both compartmental and noncompartmental pharmacokinetic analyses. Based on the calculated pharmacokinetic parameters, in vivo release profiles were simulated and compared with in vitro release profiles in three different release media. Significantly longer mean residence time (MRT) was observed after administration of the sustained-release microspheres compared with AZT powder. Significantly lower maximum (Cmax) concentration values and longer times to Cmax (tmax) values were also observed. Formulation I showed the longest MRT (4.4 h). AZT plasma concentration was maintained above the minimum effective concentration for ∼10h after administration of Formulation I. The relative bioavailability of the microsphere formulations with respect to AZT powder was not significantly different from 1. The in vitro release of the three formulations was slower in simulated gastric fluid compared with simulated intestinal fluid. The addition of enzymes and mucin to the release media significantly lowered the in vitro release rate of AZT from the microspheres formulations, but not from AZT powder. A good level of in vitro–in vivo correlation (Level A correlation) was achieved with a release medium that was composed of simulated gastric fluid with pepsin and mucin for 2h followed by simulated intestinal fluid with pancreatin and mucin for 8h. This in vitro model may be used to predict the in vivo release of AZT, in the further development of controlled-release AZT formulations.