Pharmacokinetics of prednisolone in man during acute and chronic exposure to high altitude.

INTRODUCTION: The exposure to high altitude (H) produces several physiologic alterations which may induce changes in the pharmacokinetics of drugs. This hypothesis has been confirmed in previous studies which suggest that drugs which are highly bound to plasma proteins are most likely to exhibit altered pharmacokinetics. OBJECTIVES: To further elucidate the influence of H on pharmacokinetics, prednisolone was selected, since it is highly bound to plasma proteins, renally excreted and poorly bound to red blood cells. SUBJECTS, MATERIALS AND METHODS: Prednisolone (80 mg) was given orally to three groups of young healthy volunteers. One group was residing at sea level (L): the same volunteers were studied again after 15 hours of exposure to high altitude (3600 m, HA group), and volunteers living at H for at least six months (group HC). RESULTS: There were no statistically significant differences in the pharmacokinetic parameters calculated from plasma data in the three situations studied. When calculated from whole blood data, however, AUC and Cmax were increased and both volume of distribution and clearance diminished after exposure to H, either acute or chronically. Binding to proteins increased significantly after H exposure from 57% in group L to 75% and 94% in group H and HC, respectively. Binding to erythrocytes also increased with H exposure from 43.7% in group L to 50.6% and 61.6% in group HA and HC, respectively. The prednisolone/prednisone ratio in urine was 11.1 in group L, 7.3 in group HA and 45.6 in group HC. CONCLUSION: Since prednisone has very little intrinsic glucocorticoid activity and has to be converted to prednisolone for therapeutic effect, the alteration of the prednisolone/prednisone ratio, as a result of high altitude exposure could be clinically relevant. Additional experiments are desirable to further evaluate this observation.

Effects of high altitude exposure on the pharmacokinetics of furosemide in healthy volunteers.

INTRODUCTION: A cascade of pathophysiological events occurs with the ascension to high altitude (H). We have performed studies on the effects of exposure to H on the pharmacokinetics of drugs. The hypothesis behind these studies has been that the exposure to H, which produces marked physiological changes in the body, may alter pharmacokinetics, and consequently, pharmacodynamics. Our previous studies suggest that drugs highly bound to plasma proteins are most likely to exhibit altered disposition. OBJECTIVE: In continuation of our research, we selected furosemide which is about 98% bound to plasma proteins, renally excreted and has low binding to red blood cells. SUBJECTS, MATERIALS AND METHODS: Furosemide (40 mg) was administered orally to 3 groups of young healthy volunteers. One group who had been residing at sea level (group L), the same group after 15 hours of exposure to high altitude (3,600 m, group HA) and a group of volunteers living at H for at least 6 months (group HC). RESULTS: Our results are in accordance with the most recent pharmacokinetic studies on furosemide in which a terminal half-life of approximately 20-30 h was reported. Total proteins were 9.3% and 12.7% higher in groups HA and HC, respectively, than in group L. Albumin in group HC was 8.2% higher than group L. Bilirubin increased 17.7% and 41.2% in groups HA and HC, respectively, in comparison with group L. A rapid disposition rate constant in groups HA and HC was the only pharmacokinetic parameter that was significantly different from those in group L. Concentration of furosemide in plasma water increased significantly after H exposure, thus, the binding diminished from 97.2% in group L to 95.1% and 91.1% in groups HA and HC, respectively. CONCLUSION: Exposure to H produces an increase in the free fraction of furosemide in humans, which could be of therapeutic importance.

Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude.

INTRODUCTION: Exposure of the human body to high altitude causes a number of physiological changes. In previous studies, we observed that these changes may alter the pharmacokinetics of drugs. The number of erythrocytes/mm3 increases both, after acute exposure to high altitude (HA), i.e. within 12 - 24 h after reaching high altitude (H), as well as in chronic exposure (HC) (> 10 months) to H. Also binding of drugs to biologic material may change with exposure to HA and/or HC. OBJECTIVE: Since lithium is transported into and out of erythrocytes and binds strongly to erythrocytes, but is not plasma protein-bound, we selected this drug as candidate for the present study. SUBJECTS, MATERIAL AND METHODS: Lithium carbonate 300 mg were administered orally to young healthy volunteers. One group residing at low altitude (Santiago, Chile, 600 m, group L), these same volunteers after 15 hours of exposure to high altitude (4,360 m, group HA), and volunteers living at high altitude for at least 10 months (group HC). RESULTS: We found a significant increase of both hematocrit and red blood cell count (RBC) after exposure to H, both, acute or chronic. Elimination half-life increased 64.1% in group HA and 111.4% in group HC in comparison to group L. We also found an increase in volume of distribution: + 18.9% in group HA, and + 35.8% in group HC when measured in plasma, and + 16.9% in group HA and + 18.8% in group HC when measured in whole blood. Lithium uptake by the erythrocytes increases: the value of 36.7 +/- 22.7% in Group L rose to 54.8 +/- 21.1% and to 54.6 +/- 24.2% in groups HA and HC, respectively. Total clearance decreases at high altitude, though the differences were significant only in group HC (37%). CONCLUSION: Results indicate that exposure to H produces alterations in the pharmacokinetics of lithium and that these variations may be clinically relevant.

Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.

Exposure to high altitude results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2,500 m to severe symptoms above 4,000 m. In a previous study, changes in the pharmacokinetics of meperidine were observed after exposure to high altitude. This study was conducted to investigate whether similar changes occur for acetazolamide, which is prescribed for prophylaxis of acute mountain sickness. Acetazolamide 250 mg was administered orally to young, healthy male volunteers in groups of 12 each: those residing at sea level (group L), these same volunteers on the day after arrival at high altitude (4,360 m, group HA), and volunteers living at high altitude for 10 months or longer (group HC). Serial blood samples were collected for 24 hours and acetazolamide concentrations were measured in whole blood, plasma, and plasma water. The elimination rate constant (lambda z) was significantly increased in group HA compared with group L. Clearance uncorrected for bioavailability (Cl/F) increased significantly in group HA compared with group L, and further increased in group HC. Apparent volume of distribution (Vz/F) was decreased by 17% in group HA compared with group L, and increased by 37% in group HC compared with group HA. Mean residence time (MRT) was significantly decreased in group HA compared with groups L and HC. Erythrocyte (RBC) uptake increased significantly after a significant increase in RBC count in group HC compared with group L. The extent of protein binding (EPB), however, was significantly decreased in group HA compared with groups L and HC. Free acetazolamide concentrations were significantly lower in group HC than in group L 12 hours after administration. Based on these observations, it is suggested that patients travelling to high altitude, especially altitudes above 4,000 m, should be closely monitored and acetazolamide dosage adjusted as necessary.

Urinary excretion of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.

Acetazolamide is recommended for the prophylaxis of acute mountain sickness symptoms which sets in on climbing to high altitudes (H) above 2,500 m. It is primarily excreted unchanged in urine. In a previous study, we reported on the changes in urinary excretion of meperidine and its metabolite normeperidine on exposure to high altitude. In this study, we investigated the effect on urinary excretion of acetazolamide. The study was carried out in three groups of 12 healthy male volunteers each: at sea level (group L), these same volunteers the day after arrival at high altitude of 4,360 m (group HA), and subjects residing for approximately 10 months at high altitude (group HC). Urine was collected for the periods of 0-2, 2-4, 4-8, 8-12, 12-24 and 24-36 h after peroral administration of a single 250 mg dose. Urinary pH was measured and the concentrations of acetazolamide were determined. There were no significant changes observed in the amount of acetazolamide excreted in urine over 36 h. The urinary pH ranged from 4.5 to 7.8 for L, from 4.2 to 6.9 for HA and from 3.1 to 6.7 for HC. The Fel (fraction eliminated unchanged in urine) was calculated from the amount excreted in 36 h in urine and dose, assuming a bioavailability of 1 based on literature data. No significant changes in Fel were seen.

Animal models for transdermal drug delivery.

The purpose of this investigation was to compare the permeation characteristics of two different compounds (extremely polar and nonpolar), i.e., tritium-labeled water (W) and 14C-labeled 7-hydroxycoumarin (7-OHC), among 16 different species, including human skin. Snake skin exhibited highest permeability for both W and 7-OHC. Permeability and lag time values of W and 7-OHC across Brattleboro rat and hairless guinea pig are very close to human skin. Skin thickness in micrometers (full thickness, epidermis and stratum corneum, and stratum corneum), and number of hair follicles present in each cm2 were determined for each species. There was no relationship between number of hair follicles and permeability values for both W and 7-OHC. The skin thickness (full) was related to the relative permeability values of W, whereas for 7-OHC it was not.

The effects of triethanolamine myristate, a fatty acid salt, on the availability of riboflavin in humans.

A human study examined the effect of administering a triethanolamine myristate tablet 30 min prior to or concomitantly with a fast release riboflavin tablet and a slow release riboflavin tablet. There was no significant difference between any of the treatments although treatments with the slow release riboflavin resulted in greater urinary excretion of riboflavin. It is possible that a difference may only be seen within subjects because gastric emptying has a large intraindividual variation. When triethanolamine myristate is administered to delay gastric emptying, the inhibition may be affected by the individual's normal transit rate. Another reason-might be lack of sufficient bile salts in the fasting state, reducing chyme and micelle formation, or a higher dose of triethanolamine myristate may have been needed to detect a difference.

The effects of triethanolamine myristate, a fatty acid salt, on the bioavailability of riboflavin in dogs.

A study in dogs was performed in which a physiologic approach to delaying gastric emptying was examined. Triethanolamine myristate (a fatty acid salt) was used to delay gastric emptying in hopes of increasing the bioavailability of riboflavin. A bilayer tablet consisting of triethanolamine myristate and riboflavin resulted in an absolute bioavailability of 2-3 times greater than the bioavailability of riboflavin alone. Increases in bioavailability although to a lesser extent, were also seen with the 30 min pretreatment with triethanolamine myristate. The results suggest that it was possible to delay gastric emptying.

Microemulsion technology in the reformulation of cyclosporine: the reason behind the pharmacokinetic properties of Neoral.

Management of transplant patients receiving cyclosporine therapy is complicated by interpatient and intrapatient variability in pharmacokinetic parameters caused by the drug's unpredictable bioavailability. Cyclosporine, a highly lipophilic cyclic polypeptide, has recently been reformulated using a microemulsion delivery system to improve its bioavailability. This new orally administered formulation, Neoral (cyclosporine capsules and oral solution for microemulsion), has self-emulsifying properties and spontaneously forms a microemulsion (particle size < 0.15 microns) in the aqueous fluids of the gastrointestinal tract. Clinical trials in renal transplant recipients, liver transplant recipients with external biliary diversion, and healthy volunteers have demonstrated enhanced bioavailability and greatly improved dose linearity with the cyclosporine microemulsion compared with the original cyclosporine formulation, Sandimmune (cyclosporine). The rate and extent of absorption were greater with the cyclosporine microemulsion under both fasting and nonfasting conditions, and there was a more consistent relationship between the administered dose and area under the time-concentration curve. Early clinical efficacy trials in renal and liver transplant recipients have shown no difference in the incidence or severity of drug-related adverse events. Studies on the long-term efficacy and safety of the new microemulsion formulation are ongoing.

Pharmacokinetics of meperidine in healthy volunteers after short- and long-term exposure to high altitude.

Increased numbers of erythrocytes have been shown ex vivo to increase meperidine uptake, and one of the major physiologic changes that occurs at high altitude is an increase in hematocrit and erythrocytes. A study was therefore conducted to evaluate the effects of high altitude on the pharmacokinetics of meperidine. Intramuscular doses (0.75 mg/kg) of meperidine were given to three groups of healthy volunteers (age range, 18-20 years): participants living at sea level (group L), those same participants the day after arrival at high altitude (4,360 m; group HA), and participants who had lived at high altitude for > or = 10 months (group HC). Blood samples were collected for 12 hours after drug administration. Meperidine was measured in whole blood, plasma, and plasma water. Elimination rate constant (lambda z) and clearance uncorrected for bioavailability (Cl/F) were significantly lower at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Mean residence time (MRT) was significantly higher at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Hematocrit was significantly increased at both time points at high altitude in comparison to values at sea level, and was also higher after a long-term stay at high altitude than after arrival at high altitude. Erythrocyte binding increased significantly from 41.3% at sea level to 43.8% at arrival at high altitude to 50.9% after a long-term stay at high altitude. The extent of protein binding tended to decrease with high altitude, but this decrease was not significant. Free concentrations of meperidine in plasma water measured 1, 2, and 4 hours after administration were significantly increased after 2 and 4 hours.

Pharmacokinetics of melatonin in human sexual maturation.

To determine whether melatonin pharmacokinetics change during puberty, we infused melatonin iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and measured melatonin in serum and saliva, and 6-hydroxymelatonin sulfate in urine. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 micrograms/kg. All other subjects received 0.5 microgram/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 h-1), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 h), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL).h, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 h-1). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland.

Urinary excretion of meperidine and normeperidine in man upon acute and chronic exposure to high altitude.

The urinary excretion of unchanged meperidine (M) varies with change of pH and metabolism. Since exposure of man to high altitude (H) may cause significant physiologic changes, we investigated its effects on the urinary excretion of M. The study was carried out in 3 groups of healthy, male volunteers (ages 18-20 years): at sea level (L), at 4360 m the day after arrival at H (HA), and at 4360 m in subjects residing for > 10 months at H (HC). Urine was collected for the periods of 0-4, 4-8, 8-12 and 12-24 h. Urinary pH was measured and the concentrations of M and normeperidine (N) were determined. The 24 h excretion of M and N was significantly decreased for L vs. HA and L vs. HC. Significance was also seen for the periods 0-4, 4-8 and 8-12 h. The ratio of amount excreted M/N for the 24 h period was highly significant for L vs. HA and L vs. HC. The urinary pH ranged from 5.3-5.9 for L, 5.9-7.0 for HA, and 5.1-5.7 for HC. The Fel (fraction of M eliminated in the unchanged form in urine) significantly decreased from L to HA and HC.

Application of neural networks for the prediction of human pharmacokinetic parameters.

Artificial neural network (ANN) is a method used in the prediction of response variables from a set of input and target parameters. The most commonly used network in the area of pattern recognition is the feed forward/back propagation (BPN) network. A method to predict human pharmacokinetic parameters has been proposed using BPN with a combination of physicochemical properties and animal pharmacokinetic parameters. The results were compared with in vitro estimation of the same pharmacokinetic parameters. Fourteen network models, using a variety of input variables, were developed. Protein binding, partition coefficients, dissociation constants, and the total clearance (Cltot) and volume of distribution (Vz) in rat and dog species of 41 drugs were evaluated for prediction of human total clearance and volume of distribution using the EDBD algorithm. The observations showed highest prediction for Cltot and Vz when rat and dog pharmacokinetics, combined with protein binding and partition coefficients of the drugs, were used as input parameters. Drugs with a partition coefficient (log P) < 1.17 showed predictability of 63.41% for Cltot and 48.78% for Vz. Drugs with low protein binding (approximately 20%) showed predictability of 19.51% for Cltot and 41.46% for Vz. Comparison with in vitro estimation showed no bias in the prediction of either clearance (p < 0.2) or volume of distribution (p < 0.5) by the two methods.

Meperidine uptake and binding to human blood ex vivo.

Many drugs are bound to plasma proteins (PR) and/or to erythrocytes (RBC). The RBC count may change due to physiologic factors such as exposure to high altitude, or pathologic conditions such as anemia or as consequence of cancer treatment. The purpose of the investigation was to study the influence of 1) drug concentration, and 2) number of RBC on erythrocyte uptake or binding using meperidine as a model drug (M). Human RBC concentrated blood was used and blood chemistry determined. Using human plasma (P) dilutions were made containing 9.9, 7.62, 5.87 and 4.11 million RBC mm3. The whole blood (WB) samples were spiked with M to result in 10, 25, 50, or 75 micrograms/ml. Increasing concentrations of M within each group of same RBC count did not influence percentage of erythrocyte uptake/binding. Increase in RBC count from 4.11 to 9.9 million/mm3 resulted in significant increase in erythrocyte uptake from 77.1% to 94.7% and increase in PR binding from 37.2% to 87.4%.

A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. In vitro and in vivo studies in beagle dogs.

The purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F-). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F-, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F- followed a two-compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.

Biopharmaceutic approach in designing a controlled release tablet of sodium monofluoro phosphate. Characterization of absorption sites and evaluation of modified dosage form.

Based on the results from in vivo study in dogs, it was decided to characterize the absorption sites of sodium monofluoro phosphate (NaMFP). It was hypothesized that bioavailability upon p.o. administration can be improved for controlled release dosage forms if the drug release is confined to segments of gastrointestinal tract responsible for absorption. To characterize the principal sites of absorption of NaMFP, in situ segmental absorption studies were carried out in rats. It was found that NaMFP is predominantly absorbed from the small intestine. The larger surface area and presence of alkaline phosphatase enzymes, are attributed to the higher absorption from the small intestine. Based on these results the delivery time was limited to 6 h to restrict the release of the drug within the principal sites of absorption. The dose was adjusted to 160 mg of NaMFP. After studying in vitro release profiles, the drug to polymer ratio was adjusted to 1: 1.1. The modified dosage form was finally subjected to bioavailability studies in humans. An immediate release dosage form was used to compare the efficacy in a two-period crossover study. The extent of bioavailability was 99% and the dosage form was effective in reducing the fluctuations.