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Propofol Phosphate, a Water-Soluble Propofol Prodrug:In Vivo Evaluation

Banaszczyk, Mariusz G., PhD*,; Carlo, Alison T.*,; Millan, Violeta*,; Lindsey, Adam*,; Moss, Ronald, MD*,; Carlo, Dennis J., PhD*,; Hendler, Sheldon S., MD, PhD†,

doi: 10.1097/00000539-200211000-00034
ANESTHETIC PHARMACOLOGY: Research Report
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After a single IV injection of the water-soluble propofol prodrug propofol phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1–15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose (HD50), lethal dose (LD50), and safety index (defined as a ratio: LD50/HD50) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was produced with half-lives of 5.3 ± 0.6 min in rats, 2.1 ± 0.6 min in rabbits, and 4.4 ± 2.4 min in pigs. The maximal concentration was dose and species dependent. The elimination half-life was 24 ± 12 min in rats, 21 ± 16 min in rabbits, and 225 ± 56 min in pigs. Propofol generated from PP produced pharmacological effects similar to those described in the literature. We found a correlation between PP dose and duration of sedation with propofol concentrations larger than 1.0 μg/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the administration of PP. Overall, PP, the water-soluble prodrug of propofol, seems to be a viable development candidate for sedative and anesthetic applications.

*The Immune Response Corporation, Carlsbad, California; and †Vyrex Corporation, La Jolla, California

July 10, 2002.

Address correspondence and reprint requests to Mariusz G. Banaszczyk, PhD, Chemistry Department, The Immune Response Corporation, 5935 Darwin Court, Carlsbad, CA 92008. Address e-mail to mbanaszczyk@imnr.com.

Propofol (2,6-diisopropylphenol) is a widely used IV anesthetic with a short duration of hypnotic activity, rapid emergence from anesthesia, and minimal accumulation on long-term administration (1). Some of the disadvantages of propofol, including significant bradycardia, hypertension, pain on injection, hypertriglyceridemia on prolonged administration, and the potential for pulmonary embolism (1–7), are believed to be due in large part to its oil-in-water emulsion formulation. Some of these disadvantages could be alleviated by an aqueous formulation, and a number of approaches have been reported. These approaches include aqueous formulation of inclusion complexes of propofol and hydroxypropyl-β-cyclodextrins (8,9), formulation in polysorbate 80 (10) and in Cremophor EL micelles (11), water-soluble propofol analogs (12,13), and water-soluble propofol prodrugs (14). The water-soluble prodrug approach was successfully applied in the past to several water-insoluble drugs, including antibiotics, anesthetics, and steroidal antiinflammatory drugs (15), and seemed appropriate for water-insoluble propofol. In the prodrug approach, the parent drug is modified with cleavable groups that increase the water solubility of the parent drug. Among the most common and pharmaceutically acceptable groups are phosphate monoesters and hemisuccinates—groups that can increase water solubility sufficiently without a major effect on toxicity. Our prodrug approach, as illustrated in Figure 1, was to produce propofol phosphate (PP), a well defined water-soluble prodrug of propofol that is enzymatically converted to propofol and nontoxic inorganic phosphate.

Figure 1

Figure 1

An earlier propofol prodrug, propofol sodium hemisuccinate, demonstrated protection of neuronal cells from oxidative injury in vitro(16); it was further evaluated in vitro and in vivo but was found unsuitable for commercial development as a stable aqueous formulation (Banaszczyk M, unpublished data, 2000). PP demonstrated superior stability in aqueous formulation and is enzymatically converted to two products propofol and inorganic phosphate in vitro by human placental alkaline phosphatase (Banaszczyk M, unpublished data). It is also cleaved in vivo to produce these two products. We describe here the preliminary evaluation of PP as a water-soluble propofol prodrug in mice, rats, rabbits, and pigs. We also relate PP dose to the systemic blood concentrations of propofol generated from PP and the pharmacological effects produced. This experimental work lays the foundation for future clinical evaluation of PP in the induction and maintenance of sedation and anesthesia in humans.

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Methods

All animal studies were performed in accordance with the US Department of Agriculture guidelines outlined in the Animal Welfare Act under registration No. 93-R-0278. PP sodium salt was formulated as an aqueous isotonic solution at pH 7.4 and sterile-filtered (0.2 μm) before administration to animals. Mice, rats, and rabbits were obtained from Charles River Laboratories (Wilmington, MA), and pigs were obtained from Irish Farms Products and Services (Norco, CA).

Dose-response studies were conducted in mice, rats, rabbits, and pigs, and pharmacokinetic studies were performed in rats, rabbits, and pigs. The monitoring of distinguishable levels of sedation started immediately after an IV injection and was continued for a 4-h period postinjection. The sedation level was graded according to the behavioral and reflex activity of animals injected with progressively increasing doses of PP (Fig. 2). Animals were graded as alert and normal when there was no observable change in their behavior; alert with decreased motor activity when ataxia with some ability to walk was observed; and awake and recumbent when loss (L) of righting reflex (RR) (in mice and rats) or loss of ability to stand when roused (in pigs) occurred. Animals reaching somnolence but retaining response to painful stimuli (toe pinch for mice and rats and corneal reflex for pigs) were graded as sedated with normal reflexes, whereas animals that lost response to painful stimuli were graded as sedated with decreased reflexes (anesthetic level of sedation). Death resulting from the overdose of PP was also recorded as a last level.

Figure 2

Figure 2

Hypnotic dose (HD50) and lethal dose (LD50) were obtained in 2-mo-old female CD-1 mice (24–31 g) that had access to food and water ad libitum and were kept on a 12-h light/dark cycle. During the light period, 5 groups of 9–10 mice per dose were selected randomly from a pool of 50 mice. Each group was injected IV with a selected dose of PP (Table 1) once a week for 3 consecutive weeks to cover the dose range of PP from 75 to 750 mg/kg. The speed of injection through the lateral tail vein was approximately 10 s. Each mouse received three injections in total, with a resting period of 1 wk between injections. After each injection, mice were placed on their backs frequently to test for L of RR as a measure of hypnotic activity and were also graded for the level of sedation. From the percentage of mice in each group showing L of RR for 30 s or longer, a probit analysis (SAS; SAS Institute, Cary, NC) yielded the HD50 and 95% confidence limits. The duration of sleep was recorded as the interval between the L and regain of RR. The LD50 and 95% confidence limits were determined from probit analysis of the number of mice dying at each dose. The safety index (SI) was calculated as the LD50/HD50 ratio.

Table 1

Table 1

Dose-response in rats was determined in 8-wk-old Sprague-Dawley male rats (290–330 g). Eight groups of three rats each were injected IV (tail vein) with increasing doses of PP (Table 1; doses ranging from 30 to 250 mg/kg) and monitored for levels of sedation for up to 4 h. Each rat received only one dose in the course of the study. The initial dose of 30 mg/kg (116 μmol/kg) of PP was selected as the equimolar dose to 20 mg/kg (116 μmol/kg) of a propofol dose for comparative purposes. Propofol blood concentrations produced in rats after IV administration of a 20 mg/kg propofol dose were described in the literature (17). At the 130 mg/kg dose, the pharmacokinetic samples were withdrawn at 1, 3, 5, 10, 20, 30, 60, 90, 120, and 240 min via a jugular vein catheter for 5 rats. PP was injected IV in the marginal ear veins of 4 female New Zealand White rabbits (2.8–3.1 kg). Each rabbit received only one dose. One rabbit received 64.5 mg/kg, and 3 others received 150 mg/kg. Rabbits injected with the 150 mg/kg dose had a catheter inserted into the marginal ear vein of the noninjected ear, and blood samples were withdrawn at 1, 3, 5, 10, 20, 30, 60, and 90 min after injection. PP was also evaluated in 4 8- to 12-wk-old pigs (27–33 kg)—2 White Barrow males, 1 White Barrow female, and 1 Duroc female—free from clinical signs of disease. They were housed in an outdoor pen. The pigs were fed a standard pellet diet, given water ad libitum, and fasted for 20 h before injections. Each pig was injected with one dose at a time via the ear vein once every 7 days for 4 wk with doses of 4, 14, 72, 84, and 144 mg/kg. The number of pigs injected with each dose is given in Table 1. For comparative purposes, the initial 2 doses of PP, 4 and 14 mg/kg, were selected as equimolar doses to 2.5 and 10 mg/kg of propofol, respectively, because these 2 doses were described in the literature (18). Blood samples were withdrawn from the noninjected ear, and the pigs were observed closely for 4 h and graded for the level of sedation achieved. At doses smaller than 72 mg/kg, 1 blood sample was taken from each pig before and 5–30 min after dosing. For pigs injected with 72 mg/kg, ear vein catheters were inserted, and 450-μL blood samples were withdrawn at 1, 3, 5, 10, 15, 20, 40, 60, 120, and 240 min. The extraction of propofol from blood samples was performed immediately after they were drawn to minimize conversion of PP to propofol in these samples. The analysis of propofol extracted from blood samples was performed on a high-performance liquid chromatography system that eluted propofol isocratically at approximately 6.2 min with water/acetonitrile/trifluoroacetic acid (550:450:1 vol/vol/vol) at a flow rate of 1 mL/min by using ultraviolet detection at 214 nm for rat and rabbit samples or electrochemical detection for pig samples (Banaszczyk M, unpublished data, 2000) (17). For each animal after IV administration, all concentration versus time profiles were analyzed by standard pharmacokinetic methods with biexponential equations; results were averaged and reported as mean ± sd.

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Results

By following well established methods for propofol (18–21), the dose-response and anesthetic activity of PP in mice, rats, rabbits, and pigs were investigated. Estimates of HD50, LD50, and SI were obtained in mice in a dose-range study from 75 to 750 mg/kg. The HD50 value was 165.4 mg/kg (0.64 mmol/kg) with the 95% confidence limits of 146.6–183.3 mg/kg (0.57–0.71 mmol/kg). The LD50 value was 600.6 mg/kg (2.3 mmol/kg) with the 95% confidence limits of 563.7–641.9 mg/kg (2.2–2.5 mmol/kg). The SI, calculated as LD50/HD50, was 3.6.

PP was converted to propofol in all the species studied, as evidenced by the dose-dependent behavioral changes of progressively increasing levels of sedation (Fig. 2) and measurable propofol concentration in blood in pharmacokinetic studies (Fig. 3). A single IV injection of increasing doses in mice, rats, rabbits, and pigs produced the dose responses shown in Figure 2. Mice given a 125 mg/kg dose showed signs of sedation by becoming ataxic, whereas doses less than 125 mg/kg had no apparent effect. Doses larger than 125 mg/kg produced increasing levels of sedation (Fig. 2) and increasing duration (Table 2) in a dose-dependent manner, with lethality first encountered at 525 mg/kg. In rats, doses smaller than 30 mg/kg had no effect, whereas doses larger than 50 mg/kg produced increasing levels of sedation and duration, with the first lethality encountered at 200 mg/kg. The one rabbit injected with 64.5 mg/kg had no immediate response but became slightly ataxic 6.9 min after injection. The rabbit remained slightly ataxic until 63.2 min after injection and then appeared normal. All three rabbits injected with 150 mg/kg had no noticeable reaction immediately after injection. The rabbits showed a decrease in the rate of nose twitch 6.8 ± 3.2 min after injection and became lethargic at 20.0 ± 8.3 min, without reaching somnolence (eyes completely open). The rabbits remained slightly lethargic (mild sedation) until they died 158 ± 66 min after injection. A gross necropsy of rabbits (150 mg/kg dose; 3/3) and rats that died at large doses (200 mg/kg, 1/3; and 250 mg/kg, 3/3) revealed a normal liver, heart, kidney, and spleen, with some hemorrhaging in the lungs. Doses larger than 150 mg/kg were not studied in rabbits because of frequent mortality at 150 mg/kg and lack of significant sedation, possibly because of low sensitivity to general anesthetics and an unusually high sleeping threshold (18,21).

Figure 3

Figure 3

Table 2

Table 2

Increasing doses from 4 to 144 mg/kg in pigs produced the dose responses shown in Figure 2; onset and duration data are presented in Table 1. No effect was observed in the pigs injected with 4 mg/kg. The 14 mg/kg dose produced ataxia. Propofol blood concentrations at 60 min were small: 0.13 and 0.14 μg/mL for the 4 and 14 mg/kg doses, respectively. At the 72 mg/mL PP dose, the propofol concentration reached 1.3 μg/mL at 6.7 ± 5.4 min and remained >1 μg/mL for approximately 60 min (Fig. 3). Somnolence and good muscle relaxation were induced in the pigs injected with 72 and 84 mg/kg. These pigs recovered within 4 h, appearing awake and normal, and eagerly returned to their normal feeding schedule. The 144 mg/kg PP dose produced somnolence, with good muscle relaxation, adequate sedation, and normal reflexes 1 min after infusion, but induced bradycardia and apnea at approximately 15.5 min, in addition to a brief loss of corneal reflex. This pig was manually resuscitated (chest compressions without intubation) for 125 min. The pig first regained normal corneal reflex, followed by recovery of auditory reflex and spontaneous breathing, and became awake but recumbent at 270 min. The pig could not stand on her own 5 h after infusion but appeared normal when observed 24 h after injection. At the 144 mg/kg PP dose, propofol blood concentrations were consistently above the waking threshold of 1.0 ± 0.3 μg/mL (Fig. 3, Table 2) for 4 h. Because of an inability to intubate and support lung function, further injections at this dose were not attempted.

The onset and duration of sedation data for mice, rats, rabbits, and pigs are presented in Table 1. The onset of sedation was dose dependent in all species. In mice, the onset values varied from 6.1 ± 1.7 min to 2.7 ± 0.4 min postinjection for the small and large doses, respectively. In rats, the onset values ranged from 10.6 ± 2.9 min to 4.4 ± 1.0 min for the small and large doses, respectively. The onset and duration of sedation could not be studied in rabbits because of the lack of adequate sedation. In pigs, the onset values ranged from 3.0 ± 0.5 min to 1.0 min for the small and large doses, respectively. The duration of the effect was also dose dependent and correlated well with increasing doses (correlation coefficient ≥0.7;P ≥ 0.007) for all species except of rabbits.

On the administration of PP in rats, rabbits, and pigs, propofol blood concentration was followed in time at selected doses and is presented in Figure 3. Some estimates of pharmacokinetic variables are shown in Table 2. The pharmacokinetic profiles of PP appeared different from those described in the literature for propofol (20–23) for the respective species. On the administration of comparable doses in rats, rabbits, and pigs, propofol blood concentrations ranged from 1.0 to 10 μg/mL, with peak (Cmax) values of 9.6 ± 2.1 μg/mL, 7.7 ± 3.2 μg/mL, and 2.9 μg/mL, respectively. The propofol Cmax values were reached in times (Tmax) ranging up to 16.1 min, with propofol production half-lives [T1/2(α)] ranging up to 5.3 min. Propofol elimination half-lives [T1/2(β)] were comparable in rats and rabbits (24 ± 12 min versus 21 ± 16 min) but were much larger in pigs (225 ± 16 min and 275 min) at both doses. Propofol blood concentrations at waking were 0.9 ± 0.8 μg/mL and 1.0 ± 0.3 μg/mL in rats and pigs, respectively.

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Discussion

The economic and clinical pressure to provide water-soluble anesthetics has renewed interest in designing analogs and prodrugs of the most popular one, propofol (3,12–14,24,25). We have developed a water-soluble prodrug of propofol, PP (Fig. 1), and evaluated it in several studies. PP is formulated in water as the sodium salt (3.1% wt/vol; pH 7.4) and sterilized by filtration (0.2 μm), and then it is ready for IV administration; this is in contrast to a current propofol formulation (Diprivan and other generic formulations) that requires oil, solubilizing agents, and an emulsification process that is hard to control (26).

PP was administered IV in mice, rats, rabbits, and pigs and was shown to be converted to hypnotically active propofol. In mice, the PP HD50 was found to be 640 μmol/kg and was approximately 10 times larger than the HD50 values reported for propofol: 66.64 μmol/kg (18) and 68 μmol/kg (12). The PP HD50 value implies that achieving the same levels of hypnosis as with propofol will require the administration of approximately 10 times larger doses of PP. The PP LD50 in mice was found to be 2.3 mmol/kg, which is, again, approximately 10 times larger than the LD50 value of 0.23 mmol/kg reported for propofol (18) and is suggestive of less toxicity than that of propofol. Subsequently, the SI in mice remained comparable to that of propofol—3.6 vs 3.40 (18) and 3.5 (19) —simply because both the HD50 and LD50 values for PP were changed by the same factor of 10, resulting in the SI, expressed as a ratio of HD50/LD50, remaining unchanged. In rats, PP seems also less potent and less toxic than propofol. A PP dose of 30 mg/kg (116 μmol/kg), which is equimolar to 20 mg/kg (116 μmol/kg) of propofol, produced no effect (Table 1). A 130 mg/kg (499 μmol/kg) dose, which is 18 times larger than the reported propofol HD50 of 5 mg/kg (28 μmol/kg) (18) and 3 times larger than the propofol LD50 of 30.28 mg/kg (169.9 μmol/kg) (18), was well tolerated (n = 5) and produced sedation without a single lethality. In rabbits, lethality (3/3) was encountered at a 150 mg/kg (581 μmol/kg) PP dose, but this was not surprising because of the earlier report describing the same lethal outcome in rabbits (6/6) that achieved light anesthesia of very short duration and little reflex depression at the 3 studied propofol doses of 5, 10, and 15 mg/kg (18). In pigs, PP seemed less potent and less toxic. The PP dose of 4 mg/kg (15 μmol/kg), which is nearly equimolar to 2.5 mg/kg (14 μmol/kg) of propofol, had no hypnotic effect, and the propofol blood concentration was less than 1 μg/mL. The PP dose of 14 mg/kg (54 μmol/kg), which is nearly equimolar to the largest propofol dose reported in the literature of 10 mg/kg (56 μmol/kg) (18), produced only ataxia and propofol blood concentrations again less than 1 μg/mL. Results in pigs at both doses indicate decreased potency, consistent with the observations in mice and rats. PP 72 mg/kg doses, which were five times larger than the largest dose of propofol described in the literature, produced sedation and propofol blood concentrations more than 1 μg/mL and were well tolerated. The 144 mg/kg dose of PP, administered to 1 pig, was 10 times larger than the largest propofol dose reported and produced an anesthetic level of sedation and no lethality. It would seem appropriate to say that in pigs, PP might also be less toxic, although very small numbers of pigs were studied, and caution should be exercised in generalizing this conclusion for observations in pigs. Certainly, propofol at 100 mg/kg (10 times the largest reported dose of propofol in pigs) would produce lethal results. Thus, at least in mice, rats, and pigs, because of a combination of PP’s lower hypnotic activity and lower toxicity, it is possible to administer large enough doses of PP to achieve the same level of sedation as is possible with propofol.

Studies with propofol showed a correlation between propofol dose and the duration of sleep (18). In our studies, a similar correlation between PP dose and sleep duration was established, thus leading to the conclusion that, in a given species, the pharmacokinetic profile is the major contributing factor to performance of this drug, i.e., onset, duration, and recovery. All the species showed dose-dependent onset, depth of sedation (Fig. 2), and duration of sedation (Table 1). The onset of sedation ranged from a minute to several minutes and was much slower than that of propofol. The onset of sedation for propofol is typically <10 seconds in mice and rats (18). The onset value seemed to plateau at large doses, possibly because of enzymatic saturation. At saturation, propofol cannot be produced any faster, and, therefore, the onset value reaches its limits in a given species. Depth of sedation ranged from mild ataxia at small doses, to deep sedation with loss of reflexes and no response to painful stimuli at intermediate doses, to apnea, bradycardia, and lethality at large doses. Duration of sedation correlated well with dose (linear regression, r2 ≥ 0.7;P < 0.05) in mice, rats, and pigs. In addition, the duration of sedation induced with PP seemed longer than with propofol. In mice, the duration of sedation induced with PP at a 2 × HD50 (330 mg/kg) dose was much longer than that with propofol at the equivalent dose (2 × HD50 [propofol] = 26 mg/kg): 86.3 ± 32.4 minutes versus 5.6 ± 1.3 minutes (18). In rats, at a 130 mg/kg (499 μmol/kg) dose, the sedation was induced and maintained for 92.7 ± 33.5 minutes without any lethality. Such a long duration could not be achieved by bolus injection of propofol, because even at a dose of 30 mg/kg (a dose close to the propofol LD50 of 30.28 mg/kg), the duration was only 26.36 ± 6.28 minutes (18). The increase in duration of propofol- induced sedation, however, could be achieved by infusion of additional amounts of propofol at precisely determined use rates (18). The duration was not studied in rabbits and could not be compared in pigs because of lack of propofol data in this species. The recovery was uneventful, with the exception of rabbits. A lethal effect was obtained in rabbits and, at large doses, in rats when respiratory arrest occurred and lung function was not supported. A similar lethal outcome in rabbits was noted in the original propofol article (18). Gross necropsy revealed some lung inflammation; the other organs were normal. No signs of any delayed toxic effect were seen in the remaining animals, which all recovered and were alert and keen to drink and eat shortly after regaining the ability to walk.

Propofol blood concentrations after the administration of PP were determined over time, and the results are presented in Figure 3 and Table 2. The onset, duration, and recovery can be explained in pharmacokinetic terms. The propofol concentration has to reach above a certain threshold value in blood to elicit the onset of sedation, persist above that threshold to produce duration, and decrease below that threshold to initiate recovery. In the initial propofol production and distribution phase (α), the propofol concentration was increasing with the estimated T1/2(α) (in minutes) for all the species (Table 2). These half-lives were comparable to those found in rabbits and pigs on the administration of propofol but were increased in rats. In the second elimination phase (β), after reaching the Cmax, the propofol concentration decreased at slightly slower rates when propofol was produced from PP than those of propofol on the administration of propofol. T1/2(β) values in rats and rabbits were comparable to the published values for propofol (18,20). The T1/2(β) in pigs was much higher than the published value for propofol: 224.8 ± 55.7 minutes versus 57.4 ± 4 minutes (19). The higher T1/2(β) in pigs implies slower recovery, which could be advantageous for long-term maintenance of sedation and anesthesia. At 72 and 144 mg/kg in pigs, the T1/2(β) values were similar. With a slow clearance effect in pigs, the propofol concentration remained above the waking threshold for several hours and decreased gradually, in contrast to the fast clearance in rats and rabbits (Fig. 3). The gradual decrease is possibly due to a combination of the two factors: propofol production and elimination rates. In the initial α phase, the propofol production rate exceeds the elimination rate, and, therefore, increasing levels of propofol are observed. At Tmax, when the propofol concentration reaches Cmax in the blood, the rate of propofol production equals the rate of propofol elimination. Shortly after that time, the propofol production rate starts decreasing, mainly because of a gradually decreasing concentration of PP, and the elimination rate starts gradually exceeding the propofol production rate; therefore, a very gradual decline in propofol concentration is observed over an extended period of time. Eventually, the pool of PP will be depleted, the propofol production will cease, and the elimination rate will decrease to the normal values that were observed in rats and rabbits. Unfortunately, the sampling period was too short and the doses too large to reach a normal propofol elimination phase, and more detailed studies may be necessary at several smaller doses to establish the dose effect on the propofol elimination rate and other pharmacokinetic variables. The enzymatic saturation seen in pigs was not observed in rats and rabbits at the doses for pharmacokinetic studies; however, enzymatic saturation would be expected at larger doses. Waking propofol blood concentrations after the administration of PP were smaller in rats but were comparable in pigs to the propofol waking values after propofol administration in the corresponding species (21).

Overall, the SI of the water-soluble prodrug of propofol, PP, was comparable to that of propofol. The decreased potency and decreased toxicity of PP allowed the administration of larger PP doses to attain the same level of sedation as with propofol. At large enough PP doses, propofol was released at anesthetic concentrations, resulting in anesthetic-level sedation. Future studies in humans are required to better understand the clinical utility of PP. These studies suggest that PP can be used to induce and maintain sedation and anesthesia in laboratory animals; however, extrapolation to the clinical situation must be done cautiously, because pharmacokinetic/pharmacodynamic variables in different species may vary significantly.

We thank Dr. Michael Peck and Dr. Charles Lollo, for helpful discussions; Bob Sargent, E. Gouveia, and D. Bassett, for animal handling; and D. P. Wu, for formulation of PP for the pig study.

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