Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Systemic bioavailability and pharmacokinetics of the doxylamine-pyridoxine delayed-release combination (Diclectin).

BACKGROUND: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. OBJECTIVES: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. METHODS: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. RESULTS: The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. CONCLUSION: There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.

[Comparative pharmacokinetics and relative bioavailability of magnesium-containing drugs].

Pharmacokinetics of magnesium ions after single peroral administration of Magnelis B6 and Magne B6 coated tablets (magnesium dose, 48 mg) was studied in rabbits. In the blood plasma, the level of magnesium ions was very low compared to the endogenous level, which did not allow the drug bioavailability to be reliable evaluated. At the same time, the level of magnesium ions was reliable determined in the daily urine of test animals. The relative bioavailability of magnesium for Magnelis B6 versus Magne B6 was estimated at 98.93 +/- 12.45% (average +/- SD).

Transport of high concentration of thiamin, riboflavin and pyridoxine across intestinal epithelial cells Caco-2.

In this study, we examined the intestinal uptake of thiamin (vitamin B(1)), riboflavin (vitamin B(2)) and pyridoxine (vitamin B(6)) administered at high concentration using intestinal epithelial Caco-2 cells as an in vitro model of drugs and food absorption. The effect of vitamin concentration, culture age, transport direction and incubation temperature on vitamin transport was determined. The vitamin transport was expressed as an apparent permeability coefficient and changes in cumulative fraction transported across epithelial membrane in time. It was found that transepithelial transport of these vitamins is dependent on the experimental factors. At low concentrations an active transport mechanism was observed, whereas at high vitamin concentration a passive transport dominated. At high vitamin concentration the transepithelial flux of vitamins in both directions was similar, which proves the mechanism of passive transport.

Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6.

Erymet is a new therapy resulting from the encapsulation of a methionine gamma-lyase (MGL; EC number 4.4.1.11) in red blood cells (RBC). The aim of this study was to evaluate erymet potential efficacy in methionine (Met)-dependent cancers. We produced a highly purified MGL using a cGMP process, determined the pharmacokinetics/pharmacodynamics (PK/PD) properties of erymet in mice, and assessed its efficacy on tumor growth prevention. Cytotoxicity of purified MGL was tested in six cancer cell lines. CD1 mice were injected with single erymet product supplemented or not with vitamin B6 vitamer pyridoxine (PN; a precursor of PLP cofactor). NMRI nude mice were xenografted in the flank with U-87 MG-luc2 glioblastoma cells for tumor growth study following five intravenous (IV) injections of erymet with daily PN oral administration. Endpoints included efficacy and event-free survival (EFS). Finally, a repeated dose toxicity study of erymet combined with PN cofactor was conducted in CD1 mice. Recombinant MGL was cytotoxic on 4/6 cell lines tested. MGL half-life was increased from <24 h to 9-12 days when encapsulated in RBC. Conversion of PN into PLP by RBC was demonstrated. Combined erymet + PN treatment led to a sustained Met depletion in plasma for several days with a 85% reduction of tumor volume after 45 days following cells implantation, and a significant EFS prolongation for treated mice. Repeated injections in mice exhibited a very good tolerability with only minor impact on clinical state (piloerection, lean aspect) and a slight decrease in hemoglobin and triglyceride concentrations. This study demonstrated that encapsulation of methioninase inside erythrocyte greatly enhanced pharmacokinetics properties of the enzyme and is efficacy against tumor growth. The perspective on these results is the clinical evaluation of the erymet product in patients with Met starvation-sensitive tumors.

Bioavailability of Cu, Zn and Mn from Mineral Chelates or Blends of Inorganic Salts in Growing Turkeys Fed with Supplemental Riboflavin and/or Pyridoxine.

An 84-day feeding trial was conducted in growing turkeys to measure the bioavailability of Cu, Zn and Mn from a commercial mineral chelate and corresponding inorganic salts in composite feeds containing supplemental riboflavin (B2) and/or pyridoxine (B6). A total of 320, 28-day-old British United Turkeys (BUT) were assigned to eight dietary treatments in a 2 × 4 factorial arrangement comprising two trace mineral sources: chelated trace mineral blend (CTMB) and its corresponding inorganic trace minerals blend (ITMB) fed solely or with supplements of vitamin B2 (8 ppm) or B6 (7 ppm) or 8 ppm B2 + 7 ppm B6. Each treatment was replicated four times with 10 turkeys each. It was observed that turkeys fed with diets supplemented solely with ITMB elicited higher (P < 0.05) Zn excretion than their counterparts fed with diets containing ITMB with supplements of vitamins B2 and/or B6. Manganese retention was lower (P < 0.05) in turkeys fed with diets supplemented solely with ITMB than those fed with diets containing vitamins B2 and/or B6 additives. Combination of CTMB or ITMB with B6 improved (P < 0.05) the concentration of Mn in the liver and Cu in the bone. It was concluded that the minerals in CTMB were more available to the animals than ITMB. Furthermore, vitamins B2 and/or B6 supplementation improved the bioavailability of the inorganic Cu, Zn and Mn in growing turkeys and tended to reduce the concentration of these trace elements in birds' excreta.

Bioavailability of vitamin B-6 from plant foods.

The major factors that affect bioavailability of vitamin B-6 are formation of reaction products during food processing, fiber type and content, and presence of the conjugated pyridoxine glucoside. The bioavailability of vitamin B-6 from animal products is quite high, reaching 100% for many foods. In general the bioavailability from plant foods is lower. The presence of fiber reduces the bioavailability by 5-10% whereas the presence of pyridoxine glucoside reduces the bioavailability by 75-80%. This glucoside is found in a variety of plant foods, with the highest content occurring in the crucifers. The percent of total vitamin B-6 that exists as the glucoside has been suggested to be the best indicator of bioavailability. Data from Nepalese vegetarian lactating women suggest that the low vitamin B-6 status of these mothers and their infants, as determined by their concentrations of plasma pyridoxal phosphate, may be adversely affected by the dietary intake of the naturally occurring pyridoxine glucoside.

Rapid uptake and clearance of pyridoxine by red blood cells in vivo.

There is rapid pyridoxine (PN) uptake in vitro into red cells where it is converted to pyridoxal (PL) forms. To assess uptake in vivo, the equivalent of 48.6 and 118 mumol PN were given intravenously to a healthy female subject. Vitamin B-6 compounds were measured by a Lactobacillus casei microbiological assay in blood taken 1-60 min after injection. After either injection there was a considerable amount of PN in the red cells at 1 min but by 3 min a large amount of that PN had disappeared, mostly unaccounted for by conversion to PL forms. Although there was considerably less PN at 1 min in both red cells and plasma after the smaller injection, in the next 2 min similar amounts had left the red cells (4.59 and 4.30 mumol) and plasma (9.37 and 10.09 mumol), respectively, after the injections. Red cells, as well as plasma, may be transporting PN to other sites of metabolism in tissues.

Plasma pyridoxal 5'-phosphate concentrations in obese and nonobese black women residing near Petersburg, VA.

The vitamin B-6 status of 15 obese and 15 nonobese black women aged 21-51 y who were not taking vitamin supplements was assessed by using plasma pyridoxal 5'-phosphate (PLP) measurements. Ages, heights, and ideal body weights of the two groups were similar as were reported energy, protein, and vitamin B-6 intakes obtained by using 24-h intake data collected on two nonconsecutive days separated by at least 1 wk. The reported vitamin B-6 intakes were 1.18 +/- 0.44 mg/d (means +/- SD). Plasma PLP levels in the obese and nonobese black women were similar; these levels were also similar to those observed previously for white obese and nonobese women having similar physical characteristics. All subjects had plasma PLP levels indicative of adequate status with one possible exception. Obesity did not affect the plasma PLP levels in these black women.

Bioavailability of vitamin B-6 in young and older men.

Various indexes of vitamin B-6 status have been shown to be reduced with aging. The cause for the apparent reduced vitamin B-6 status is not well understood. For direct assessment of how the bioavailability of vitamin B-6 is affected by aging, [2H]pyridoxine was orally administered to healthy men, aged 20-30 and 60-70 y, who were fed a controlled diet. No differences were observed in plasma pyridoxal 5'-phosphate concentration, erythrocyte aspartate aminotransferase activity, or plasma alkaline phosphatase activity between the two age groups. There were no age-related differences in the urinary excretion of total or [2H]4-pyridoxic acid during a 3-d collection period. Results from this study indicate that the bioavailability of vitamin B-6 is not altered with aging in free-living, healthy adult men.

Pyridoxic acid excretion during low vitamin B-6 intake, total fasting, and bed rest.

Vitamin B-6 metabolism in 10 volunteers during 21 d of total fasting was compared with results from 10 men consuming a diet low only in vitamin B-6 (1.76 mumol/d) and with men consuming a normal diet during bed rest. At the end of the fast mean plasma concentrations of vitamin B-6 metabolites and urinary excretion of 4-pyridoxic acid tended to be higher in the fasting subjects than in the low-vitamin B-6 group. The fasting subjects lost approximately 10% of their total vitamin B-6 pool and approximately 13% of their body weight. The low-vitamin B-6 group lost only approximately 4% of their vitamin B-6 pool. Compared with baseline, urinary excretion of pyridoxic acid was significantly increased during 17 wk of bed rest. There was no increase in pyridoxic acid excretion during a second 15-d bed rest study. These data suggest the possibility of complex interactions between diet and muscle metabolism that may influence indexes that are frequently used to assess vitamin B-6 status.

Effect of age on changes in plasma, erythrocyte, and urinary B-6 vitamers after an oral vitamin B-6 load.

We investigated the effect of age on indices of vitamin B-6 metabolism in 36 fasting males aged 25-35, 45-55, and 65-75 y who ingested 17.15 mumol vitamin B-6. There were no significant differences among groups in dietary vitamin B-6 intake, base-line erythrocyte pyridoxal 5'-phosphate (PLP), and total vitamin B-6 concentrations, and 24-h and base-line urinary excretion of total vitamin B-6 and 4-pyridoxic acid (4-PA). Base-line plasma PLP and total vitamin B-6 were higher (p less than 0.05) in the youngest group. Increased serum alkaline phosphatase (AP) and decreased dietary vitamin B-6 intake were correlated with decreased base-line plasma PLP and total vitamin B-6. Changes in plasma and erythrocyte PLP concentrations and excretion of 4-PA and total vitamin B-6 postload were not different among groups. Indices of vitamin B-6 absorption, phosphorylation, and excretion were not affected by age.

Inability of chronic alcoholics with liver disease to use food as a source of folates, thiamin and vitamin B6.

Absorption of folates, thiamin, vitamin B6, pantothenate and riboflavin from a natural food source--yeast--and their respective synthetic forms was studied in 37 patients with liver disease due to alcoholism, and 12 healthy, nonalcoholic subjects. All alcoholics absorbed riboflavin and pantothenate but had a significantly lowered absorption of thiamin and vitamin B6 from yeast. Alcoholics absorbed synthetic vitamin B6, but not thiamin. Ingested folylpolyglutamates (the predominant folates in yeast) could not serve as a source of folate for the alcoholics, but synthetic folylmonoglutamate served. We suggest that the folate, vitamin B6, and thiamin deficits so common in alcoholic liver disease ensue from inability to absorb these specific vitamins from foods.

The bioavailability of vitamin B6. Recent findings.

Further clarification of the bioavailability of dietary vitamin B6 requires better analytical data concerning the forms of vitamin B6 in foods as well as the overall composition of foods. The application of radioisotopic and stable-isotopic studies such as those described will provide useful information concerning the inherent bioavailability of the various vitamin B6 compounds. Additional studies should then address the influence of other dietary components on the utilization of the vitamin B6 compounds, using intrinsic and extrinsic enrichment techniques. Care must be taken in interpretation of the results of animal bioassays in the determination of the bioavailability of vitamin B6 in complex diets.

Vitamin B6 metabolism by human liver.

The B6 vitamers (pyridoxine, pyridoxamine, and pyridoxal) are primarily metabolized in liver to pyridoxal 5'-phosphate (PLP) and the deadend catabolite 4-pyridoxic acid. We have built on the elegant early work of Snell and others to describe the activities of the human liver enzymes responsible for vitamin B6 metabolism and to develop a model of the relative rates of these interconversions in vivo. This model is consistent with changes in plasma B6 after a load, the clearance of different vitamers (e.g., pyridoxine versus pyridoxal), and with the low plasma PLP in patients with cirrhosis. Because cirrhotics were found to be capable of PLP synthesis, we have used oral supplementation with pyridoxine to restore plasma PLP to the normal range, and have evaluated the effects of this intervention on amino acid metabolism. No significant differences were observed in plasma or urinary clearance of methionine (or cystathionine) after an oral load, nor in amino acid clearance from circulation after a protein load for cirrhotic patients before and after restoration of normal plasma PLP. Hence, the abnormal metabolism of vitamin B6 does not appear to be an important factor in the deranged amino acid metabolism in this disease. Nonetheless, this approach may be generally useful in assessing the importance of PLP in other abnormalities.

Vitamin B6 and cancer: adenosine-N6-diethylthioether N1-pyridoximine 5'-PO4, a circulating human tumor marker.

Studies in my laboratory on the metabolism and utilization of labeled vitamin B6 by tumor-bearing animals and tumor cells in culture have shown the production and presence in the circulation of a novel pyridoxal 5'-phosphate conjugate metabolite (1-5). Using specific radiolabeling and analytical tests, its structure was tentatively identified (now confirmed) as adenosine-N6-diethylthioether-N1-pyridoximine 5'-phosphate (4-6). The novel vitamin conjugate was isolated from the plasma of patients and control subjects following extraction with perchloric acid and separation by pair-ion HPLC. This communication reports the chromatographic separation of the novel compound and its plasma levels in control subjects, cancer patients and patients with other ailments. The results show that the novel metabolite is a circulating human tumor marker with levels of up to 4x or greater seen in cancer patients compared to controls and to subjects with other ailments. The results indicate strongly that the novel circulating vitamin B6 conjugate compound can be successfully used for the detection of different malignancies in humans by evaluating its level in circulation.

Metadoxine in the treatment of acute and chronic alcoholism: a review.

Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco-therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor aspecific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.

Determination of total pyridoxal in human plasma following oral administration of vitamin B6 by high-performance liquid chromatography with post-column derivatization.

An HPLC method for determining total pyridoxal from plasma was developed for a relative bioavailability comparison of two oral vitamin B6 (pyridoxine HCl) preparations. After cleavage of the pyridoxal-5-phosphate with the acid phosphatase enzyme, the total pyridoxal was determined by HPLC. Pyridoxal was separated on a reversed-phase column, post-column derivatized to pyridoxal-semicarbazide, and then detected by fluorescence and quantitated. The limit of detection was 2 ng/mL and interday variation (3 days) over the whole concentration range (13-215 ng/mL spiked) was < 4.1%. In the relative bioavailability study, 16 human subjects were put on a low vitamin B6 diet for a period of 3 days. On the 2nd and 3rd days, 14 blood samples were taken per subject at the same times each day. The drug was administered on the 3rd day. Total endogenous pyridoxal detected on the 2nd day varied in plasma between 13 and 17 ng/mL. Pharmacokinetic parameters corrected for background are reported for two vitamin B6 (40 mg) preparations. Briefly, the pharmacokinetic results for the Ratiopharm preparation compared with the Hoffmann-La Roche preparation are, respectively: AUC0-24, 369.2 and 352.6 ng.h/mL; AUC24-48, 1638.2 and 1662.3 ng.h/mL; net Cmax, 193.0 and 197.1 ng/mL; tmax, 1.25 and 1.44 h; and relative bioavailability, 97.9% (Westlake, 88-112%).

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Pharmacokinetics of doxylamine given as Bendectin in the pregnant monkey and baboon.

The object of the present study was to determine the maternal plasma pharmacokinetics of doxylamine (the antihistamine component of Bendectin) following Bendectin administration. Bendectin was administered daily, po, at a dosage approximately 10 times the maximum human therapeutic dosage (7 mg/kg/day) throughout organogenesis (approximately days 22 through 50 of gestation) to three cynomolgus monkeys, four rhesus monkeys, and five baboons. Two pharmacokinetic experiments were performed in each animal, one on the first day of treatment and one on the last day of treatment. Although this study was not designed specifically as a teratologic examination, no morphologic abnormalities were observed when the fetuses were examined on approximately day 100 of gestation. A single-compartment, parallel first- and second-order elimination model was used to analyze the data. Although considerable interindividual variation was evident, no significant differences between species were observed when the half-life for the absorption of doxylamine from the gut or the elimination of doxylamine and metabolites from the plasma were compared. The plasma elimination half-lives and the clearance values were not altered by the 29 days of Bendectin treatment for any of the species. Only the half-life for the absorption of doxylamine in the baboon was reduced by daily dosing with Bendectin, but this did not alter doxylamine elimination. Thus, the pharmacokinetics of doxylamine administered as Bendectin were similar in the three nonhuman primate species examined and were not altered by repeated daily administration.