QSAR of the anticonvulsant enaminones; molecular modeling aspects and other assessments.

The enaminones represent potentially useful agents for the clinical treatment in generalized tonic-clonic seizures (Epilepsia, 1993, 34(6), 1141-1145, Biopharm. Drug Disp. 2003, 397-407). A regression analysis was performed to provide a quantitative structure-activity relationship (QSAR) correlation model for prediction of activity for the anticonvulsant enaminones. Molecular modeling was performed to determine the molecular confluence of the Unverferth model (J. Med. Chem. 1998, 41, 63-73) to the enaminones. Conclusions related to the sodium channel model were assessed.

Enaminones-versatile therapeutic pharmacophores. Further advances.

Enaminones, enamines of ss-dicarbonyl compounds, have been know for many years. In our initial account (Current Med. Chem. 1994, 1, 159-175), we reported on the anticonvulsant activity of a series of enaminones, notably methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en- 1-oate, 9a (R=CH3, R1=4-Cl), which, in animal tests, compared favorably to phenytoin and carbamazepine. Since that time, further research in our laboratory and other laboratories have expanded the therapeutic potential of these compounds. In addition to new anticonvulsant derivatives, we have uncovered a novel brain transport mechanism for the enaminones and developed a preliminary regression model for further synthetic direction. These topics will each be presented and elaborated.

Biliary excretion of reduced haloperidol glucuronide.

The biliary excretion of haloperidol and reduced haloperidol were investigated in the guinea pig. Bile duct cannulated guinea pigs were administered a single intraperitoneal dose of haloperidol (1 mg/kg). Bile was continually collected over a 12-h period. Aliquots of the bile samples were analyzed by HPLC for free haloperidol and reduced haloperidol. The remaining portions of the bile samples were incubated with beta glucuronidase and reanalyzed for haloperidol and reduced haloperidol. Although no significant amount of haloperidol glucuronide was detected in the bile, a new metabolite of reduced haloperidol, reduced haloperidol glucuronide, was found. The amount of reduced haloperidol excreted in the bile as the glucuronide conjugate was significantly higher than the amount of haloperidol or reduced haloperidol. These results imply that reduced haloperidol glucuronide may play a role in the disposition of haloperidol and/or its metabolite, reduced haloperidol.

The influence of the menstrual cycle on triazolam and indocyanine green pharmacokinetics.

The aim of this study was to investigate the effects of the menstrual cycle phase on the pharmacokinetics of two high-clearance agents, triazolam and indocyanine green (ICG). Eleven nonsmoking, healthy, eumenorrheic women were enrolled in this study. Triazolam (0.25 mg) was administered orally, and indocyanine green was administered as an i.v. bolus (0.5 mg/kg) during the follicular, ovulatory, and luteal phases of a single menstrual cycle. Blood samples were collected over 10 hours for triazolam and over 30 minutes for ICG. Triazolam and indocyanine green concentrations were quantitated by electron capture gas chromatography and spectrophotometry, respectively. Noncompartmental analysis was used to determine relevant pharmacokinetics parameters, which were statistically assessed using two-way ANOVA (p < 0.05). No statistical differences for triazolam were observed. Vd/F was lower in the luteal phase (107 L) as compared to the follicular (138 L) and ovulatory (133 L) phases. Clearance of triazolam was comparable in the follicular (583 ml/min), ovulatory (565 ml/min), and luteal (538 ml/min) phases. ICG also revealed no significant differences across the phases. These results suggest that the phases of the menstrual cycle do not influence triazolam or ICG pharmacokinetics.

Plasma pharmacokinetics and urinary excretion of the polyamine analogue 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane in CD2F1 mice.

The pharmacokinetics of 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane (BE-4-4-4-4) were determined in CD2F1 female mice after administration of i.v. bolus doses of 20 mg/kg (approximately the dose lethal to 10% of the study animals, approximately LD10) as well as 15, 10, and 5 mg/kg and after s.c., i.p., or p.o. doses of 20 mg/kg. BE-4-4-4-4 in plasma and urine was derivatized with dansyl chloride and measured by gradient high-performance liquid chromatography (HPLC) with fluorescence detection. Data were modeled by noncompartmental and compartmental methods. The declines observed in plasma BE-4-4-4-4 concentrations after i.v. delivery of 20, 15, 10, and 5 mg/kg were modeled simultaneously using an interval of 2000 min between doses and were best approximated by a two-compartment, open, linear model. The time courses of plasma BE-4-4-4-4 concentrations after i.p. and s.c. delivery were fit best by a two-compartment, open, linear model with first-order absorption. Peak plasma concentrations of BE-4-4-4-4 measured following an i.v. dose of 20 mg/kg ranged between 30 and 33 microgram/ml, the terminal elimination half-life was 94 min, and the volume of distribution (Vdss) was 850 ml/kg. The plasma pharmacokinetics of BE-4-4-4-4 were linear with dose. BE-4-4-4-4 (0.5 and 2.0 microM) in mouse plasma was approximately 67% protein-bound. Bio-availabilities after i.p., s.c., and p.o. delivery were 40%, 50%, and approximately 3%, respectively. Urinary excretion of parent BE-4-4-4-4 in the first 24 h after dosing accounted for less than 30% of the delivered dose. As BE-4-4-4-4 proceeds toward and undergoes clinical evaluation, the data and analytical method presented herein should prove useful in formulating a dose-escalation strategy and, possibly, evaluating toxicities encountered.

Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice.

We defined the pharmacokinetics of paclitaxel after i.v., i.p., p.o., and s.c. administration of 22.5 mg/kg to CD2F1 mice. Additional mice were studied after i.v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 micrograms kg-1 min-1. Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CLtb) was 3.25 ml min-1 kg-1 and the terminal half-life (t1/2) was 69 min. After i.v. administration to female mice, paclitaxel CLtb was 4.54 ml min-1 kg-1 and the terminal t1/2 was 43 min. The bioavailability of paclitaxel was approximately 10%, 0, and 0 after i.p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a suspension in Klucel: Tween 80. Pharmacokinetic parameters were similar after i.v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CLtb calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques.

Phenytoin pharmacokinetics following oral administration of phenytoin suspension and fosphenytoin solution to rats.

The administration of phenytoin suspension in conjunction with enteral nutrition supplements through nasogastric (NG) feeding tubes to humans has been associated with suboptimal phenytoin absorption, subtherapeutic concentrations, and breakthrough seizures. Postulated mechanisms include chelation to proteins and electrolytes in the enteral feeding, binding to NG tubing, and alterations in gastrointestinal pH resulting in precipitation of phenytoin. The purpose of this pilot study was to evaluate the oral absorption of commercially available fosphenytoin injectable solution compared to phenytoin suspension in the rat to determine whether equivalent oral fosphenytoin and phenytoin suspension doses should be used for future human studies of fosphenytoin oral absorption in the presence of concomitant enteral nutrition. A single oral 30 mg/kg phenytoin equivalents dose of either commercially available fosphenytoin or phenytoin suspension was administered to male Wistar rats following an overnight fast. Blood samples (0.3 ml) for phenytoin plasma concentration were obtained from a jugular vein catheter at baseline and 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12 and 24 h post-study drug administration and analyzed by high performance liquid chromatography (HPLC) (CV% < 6). Mean phenytoin Cmax was 85% [corrected] (P = 0.010) higher in fosphenytoin vs phenytoin treated rats. Tmax was 2.4 h (62%, P=0.021) shorter in fosphenytoin vs phenytoin treated rats. No significant differences in AUClast were found. The presence of a phosphate ester moiety does not appear to inhibit the appearance of phenytoin following oral administration of fosphenytoin. Phenytoin plasma concentration profiles following oral administration of fosphenytoin are characterized by higher Cmax and shorter Tmax values relative to oral administration of phenytoin suspension.

Enhancing the permeation of marker compounds and enaminone anticonvulsants across Caco-2 monolayers by modulating tight junctions using zonula occludens toxin.

Zonula occludens toxin (Zot), a protein elaborated from Vibrio cholerae, has been shown to be capable of reversibly opening tight junctions between intestinal cells The objective of this study was to examine the effect of Zot on the flux of various molecules across Caco-2 cell monolayers. In addition, the transport of a series of anticonvulsants, the enaminones was also evaluated in the presence of Zot. The flux of [(14)C]mannitol, [(14)C]inulin and various enaminones across Caco-2 cell monolayers (n=6) was examined after pre-incubation for 1h with Zot (0 or 4000ng/ml) or phosphate-buffered saline (PBS). At the end of the incubation period, the flux of radiolabeled compounds or enaminones (1x10(-4)M) was assessed over a 2-h period. In addition, dose-response studies with Zot (0, 1000, 2000 or 4000ng/ml) were performed using mannitol. The flux of both mannitol and inulin significantly increased (P<0.05) in the presence of Zot. The transport of the enaminones with Zot ranged from 9.42 to 26.83x10(-5)cm/s vs. 4.68 to 13.83x10(-5)cm/s without Zot. Zot significantly increased the transport of all agents tested. This suggests that the co-administration of drugs with Zot may be a useful delivery strategy to increase the intestinal permeability and hence oral absorption of poorly bioavailable agents.

Sensitive electrochemical high-performance liquid chromatography assay for the simultaneous determination of haloperidol and reduced haloperidol.

An electrochemical HPLC method for the simultaneous determination of haloperidol and reduced haloperidol in plasma is presented. Chlorohaloperidol serves as the internal standard. A cyanopropyl bond elut column was used for sample preparation. The eluate was evaporated and reconstituted with mobile phase and injected onto a nitrile bonded column. The chromatographic system consisted of an ESA Coulochem detector operated in the screen mode. Intra- and interassay coefficients of variation for both compounds were less than 7%, with a sensitivity limit of 20 pg on the column. A plasma level-time profile is presented to illustrate the sensitivity and applicability of this assay in small animal and human pharmacokinetic studies.

Application of computer-assisted radiotelemetry in the pharmacokinetic and pharmacodynamic modeling of procainamide and N-acetylprocainamide.

The cardiovascular pharmacodynamics (PD) of procainamide and N-acetylprocainamide have not been well characterized in small rodents without the presence of anesthesia or restraint. This study was undertaken to examine the pharmacokinetics (PK) and PD relationship of procainamide and N-acetylprocainamide by use of electrocardiogram (ECG) telemetry in unrestrained rats. Male Sprague Dawley rats received the following treatments: vehicle, procainamide 50 and 100 mg/kg and N-acetylprocainamide 50 and 100 mg/kg via intraperitoneal (i.p.) administration. Blood samples were collected over 8 h and subsequently analyzed. PD measurements (PQ, QS, QR, QT, RR, and HR) were collected prior to dosing and over a 24 h period. Mean PK parameters after the 50 mg/kg dose were as follows: Cls/Fprocainamide = 86.42 mL min-1 kg-1, Cls/FN-acetylprocainamide = 36.62 mL min-1 kg-1, Vdprocainamide = 10.42 L/kg, and VdN-acetylprocainamide = 5.91 L/kg. The relationship between concentration (procainamide or N-acetylprocainamide) and effect (percent change QT interval) was best described by an Emax model for procainamide (EC50 = 445 ng/mL; Emax = 30.09%). These results approximate ECG changes noted in procainamide clinical studies, suggesting that telemetry can be used as a predictive tool of efficacy. Furthermore, the proposed PK-PD model describes the electrophysiological effects associated with procainamide.

Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants.

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood-brain barrier (BBB) transport might be influenced by the presence of an efflux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 microM) and probenecid (100 microM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 microM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated mice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviolet and fluorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid significantly ( p>0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically significant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (-/-) mice brains were significantly higher ( p<0.05) compared with those in mdr 1 a/b (+/+) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may influence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.

Evaluating a possible pharmacokinetic interaction between remifentanil and esmolol in the rat.

Remifentanil (Ultiva) is a novel, ultra-short-acting opioid which has recently been approved for use as an analgesic during induction and maintenance of general anesthesia. Esmolol is a short-acting beta-blocker used during surgical procedures to reduce heart rate and blood pressure. Both drugs are metabolized by nonspecific esterases in the blood and other tissues and may be administered concomitantly during surgery. The goal of this study was to determine if coadministration of esmolol significantly alters the pharmacokinetics of remifentanil in the rat. Two groups of rats were dosed with remifentanil [25 micrograms/kg/min (n = 8)] and remifentanil plus esmolol [25 and 200 mg/kg/min (n = 7)] for 20 min. Cardiovascular measurements were collected continuously over the course of the study. Serial blood samples (12) were collected over 25 min into test tubes containing 0.5 mL of acetonitrile. Blood samples were extracted (liquid-liquid) with methylene chloride and then analyzed by a validated GC-MS assay. Compartmental data analysis was performed using PCNONLIN. The mean(+/- SD) for Cl and t1/2 observed in treatment I were 390(+/- 98) mL/min/kg and 0.69(+/- 0.27) min and in treatment II were 421(+/- 164) mL/min/kg and 0.56(+/- 0.22) min, respectively. Comparison of clearance, volume of distribution, and terminal half-life between the two groups showed that coadministration of esmolol had no significant (p < 0.05) effect on the pharmacokinetics of remifentanil in the rat.

Evaluation of "external" predictability of an in vitro-in vivo correlation for an extended-release formulation containing metoprolol tartrate.

The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended-release tablet from a 3-kg small batch (I) to a 50-kg large batch (II). The second study examined the influence of scale and processing changes [3-kg small batch with fluid bed granulation and drying (III); 80-kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I-V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were <10% for C(max) and area under the curve (AUC) of concentration versus time for I, II, and IV. The C(max) for III was slightly underestimated (11.7%); however, the PE of the AUC was <10%. Formulation V displayed a PE for C(max) > 20% and an AUC within 5% of observed values. The low PEs for C(max) and AUC observed for I-IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale-up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific.

A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics.

UNLABELLED: Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. OBJECTIVE: The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. RESULTS: Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. CONCLUSION: Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.

Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans.

Following 49 h of sleep deprivation, 37 healthy males ingested either 2.1, 4.3, or 8.6 mg*kg-1 body weight of caffeine in a randomized double-blind design. Subjects were sleep deprived for additional 12 h and venous blood samples were collected intermittently. Caffeine and primary metabolite concentrations were determined by HPLC. Pharmacokinetics were computed using the Lagran computer program. The ratio of the primary human metabolite, paraxanthine, to caffeine was used to estimate the rate of metabolism. There was a significant (p < 0.05) and disproportional increase in the dose normalized caffeine AUC and a significant decrease in its clearance associated with increasing dose. In addition, the paraxanthine to caffeine ratio significantly decreased with an increase in dose, indicating that the rate of caffeine metabolism decreased. These results demonstrate that under the conditions of severe sleep deprivation caffeine exhibits dose-dependent pharmacokinetics. In addition, these results are consistent with a model of capacity-limited metabolism.

Rapid method for the quantitation of mivacurium isomers in human and dog plasma by using liquid chromatography with fluorescence detection: application to pharmacokinetic studies.

A simple, selective and specific liquid chromatography method was used to simultaneously determine the cis-cis, cis-trans and trans-trans isomers of mivacurium in human and dog plasma. Solid phase extraction was used to separate interfering endogenous products from the compounds of interest. Fluorometric detection was evaluated at excitation and emission maxima of 280 and 325 nm. The calibration curves were found to be linear in the range 50-500 ng ml-1. The method was applied to plasma samples collected from a human and dog study and was found to be satisfactory. Excellent recovery, linearity, accuracy and precision were achieved by the assay for each isomer.

Determination of the nutraceutical, glucosamine hydrochloride, in raw materials, dosage forms and plasma using pre-column derivatization with ultraviolet HPLC.

A selective and specific high performance liquid chromatography method was developed to quantitate glucosamine hydrochloride in raw materials, dosage forms and plasma. Reverse phase chromatography using pre-column derivatization with phenylisothiocyanate, and ultraviolet detection (lambda = 254 nm) was used to quantify the eluate. The mobile phase consisted of MeOH/H2O/CH3COOH (10:89.6:0.04) and was pumped at a flow rate of 1.2 ml/min. The standard curves for glucosamine hydrochloride showed linearity (r > or = 0.99) over the selected concentration range from 6.65 to 16.63 microg/ml for raw materials and dosage forms. The precision of the dosage form assay, expressed as the % relative standard deviation (R.S.D.), was < 5% at all concentrations. The intra-day and inter-day accuracy, as indicated by the relative error (R.E.), ranged from - 2.54 to 2.70% for glucosamine hydrochloride. For the plasma assay, beagle dog plasma was used to prepare standard curves in the concentration range of 1.25-20 microg/ml. Precipitation of plasma proteins was accomplished with acetonitrile to separate interfering endogenous products from the compound of interest. The supernatant was derivatized using phenylisocyanate in phosphate buffer (pH = 8.3) and subsequently evaporated to dryness under a nitrogen stream at 42 degrees C. The residue was dissolved in 250 microl mobile phase and injected onto the chromatographic system. The assay was linear in concentration ranges of 1.25-20 microg/ml (r > or = 0.999). Intra- and inter-day precision was < or = 5.23 and 5.65%, respectively and the intra- and inter-day accuracy, indicated by R.E., ranged from - 8.6 to 10.35%. The method was found to be specific and with excellent linearity, accuracy and precision and is well suited for the quantitation of glucosamine hydrochloride in raw materials, dosage forms, and pharmacokinetic studies.

Determination of remifentanil, an ultra-short-acting opioid anesthetic, in rat blood by high performance liquid chromatography with ultraviolet detection.

Remifentanil is an ultra-short-acting opioid under evaluation for use during surgical procedures which require opioid analgesia or anesthesia. It has an N-substituted methyl propanoate ester group which is highly susceptible to clevage by blood and tissue esterases as well as to chemical hydrolysis. A selective and specific high performance liquid chromatography method was developed to quantitate remifentanil in rat blood. A liquid-liquid extraction method using n-butyl chloride was used to separate interfering endogenous products from the compound of interest. Reverse phase chromatography with ultraviolet (lambda 210 nm) detection was used to quantitate the eluate. The calibration curves were found to be linear in the range 2.5-250 ng ml-1. Intra-day assay variability was 15% or less for all standards evaluated. The method was applied to blood samples collected from a short-term infusion study in rats. Good recovery, linearity, accuracy and precision were achieved with the assay.

Effects of chronic hypoxia on the pharmacokinetics of caffeine and cardio-green in micro swine.

METHODS: The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected. RESULTS: Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased. CONCLUSION: These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations.

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open, randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by the f2 metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean Cmax and AUC(inf) for the small batch of propranolol were 79.0 microg/L and 536 microg/L/hr, and for the large batch they were 83.5 microg/L and 575 microg/L/hr. Cmax and AUC(inf) for the small batch of metoprolol were found to be 95.5 microg/L and 507 microg/L/hr and for the large batch, 95.1 microg/L and 495 microg/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for lnCmax, and lnAUC(inf) for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.