Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs.

Vitamin B6 has been known to possess antiemetic effects since 1942. This water soluble compound has several forms in the circulation including pyridoxine, pyridoxal, and pyridoxal phosphate. The active antiemetic form of vitamin B6 is unknown. This was a pre-specified substudy of a randomized, placebo-controlled trial comparing the antiemetic effect of the doxylamine-vitamin B6 combination (Diclectin®) (n = 131) to placebo (n = 126) in women with nausea and vomiting of pregnancy. Serum concentrations of pyridoxine, pyridoxal, and pyridoxal 5' phosphate (PLP) and doxylamine were measured on Days 4, 8, and 15. With Diclectin® exhibiting a significant antiemetic effect in pregnancy, serum concentrations of pyridoxine were unmeasurable in almost all patients and those of pyridoxal were undetectable in half of patients. In contrast, PLP was measurable at sustained, stable steady-state levels in all patients. Our data suggest that there is a correlation between PLP levels and PUQE score of morning sickness symptoms when pyridoxine and pyridoxal levels are undetectable, and hence they might be prodrugs of PLP, which may be the active antiemetic form of vitamin B6.

Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; implications for pharmacotherapy in pregnancy.

Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single-center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine-pyridoxine 10 mg-10 mg delayed-release tablets. Healthy males (n = 12) and non-pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0-t for each analyte. Females had significantly larger AUC0-t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine-pyridoxine.

Methoctramine reveals heterogeneity of M2 muscarinic receptors in longitudinal ileal smooth muscle membranes.

Direct binding studies on longitudinal ileal and atrial muscarinic receptors revealed that most of the ileal or atrial selective antagonists identified in functional studies did not differentiate between these muscarinic receptors in direct binding studies. Methoctramine, an atrial selective muscarinic receptor antagonist in functional studies was, however, able to partially discriminate between these two receptors in our binding studies. Furthermore the binding data obtained using this compound indicated that longitudinal ileal muscarinic receptors were heterogeneous. The predominant population of ileal muscarinic receptors displayed a similar pharmacology to the cardiac type M2 muscarinic receptor. The minor population of muscarinic receptors identified in binding studies displayed a similar pharmacology to the ileal muscarinic receptor identified in functional studies and were pharmacologically similar to the exocrine gland type M2 muscarinic receptor.