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Prostaglandin F2α 1-ethanolamide (prostamide F2α) is a potent ocular hypotensive agent in animals and represents a new class of fatty acid amide compounds. Accumulated evidence indicated that anandamide, an endogenous bioactive ligand for cannabinoid receptors, may serve as a common substrate to produce all prostamides, including prostamide F2α. After incubation of anandamide with cyclooxygenase 2 (COX-2), the reaction mixture was profiled by HPLC and an intermediate metabolite was discovered and characterized as a cyclic endoperoxide ethanolamide using HPLC-tandem mass spectrometry. Formation of prostamide F2α was also demonstrated when the intermediate metabolite was isolated and incubated with prostaglandin F synthase (PGF synthase).These results suggest that the biosynthesis of prostamide F2α proceeds in two consecutive steps: oxidation of anandamide to form an endoperoxide intermediate by COX-2, and reduction of the endoperoxide intermediate to form prostamide F2α by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H2.

We investigated the formation of PGF2α 1-ethanolamide, PGE2 1-ethanolamide, and PGD2 1-ethanolamide (prostamides F2α, E2, and D2, respectively) in liver, lung, kidney, and small intestine after a single intravenous bolus administration of 50 mg/kg of anandamide to normal and fatty acid amide hydrolase knockout (FAAH −/−) male mice. One group of three normal mice was not dosed (naïve) while another group of three normal mice received a bolus intravenous injection of 50 mg/kg of anandamide. Three FAAH −/− mice also received an intravenous injection of 50 mg/kg of anandamide. After 30 min, the lung, liver, kidney, and small intestine were harvested and processed by liquid-liquid extraction. The concentrations of prostamide F2α, prostamide E2, prostamide D2, and anandamide were determined by HPLC-tandem mass spectrometry. Prostamide F2α was detected in tissues in FAAH −/− mice after administration of anandamide. Concentrations of anandamide, prostamide E2, and prostamide D2 in liver, kidney, lung, and small intestine were much higher in the anandamide-treated FAAH −/− mice than those of the anandamide-treated control mice.This report demonstrates that prostamides, including prostamide F2α, were formed in vivo from anandamide, potentially by the cyclooxygenase-2 pathway when the competing FAAH pathway is lacking.

Objective: To determine the pharmacokinetic and pharmacodynamic interaction between oral tazarotene and an oral contraceptive containing norethindrone I mg and ethinylestradiol 0.035mg (Ortho-Novum® 1/35). Design: Two separate open-label, parallel-group, single-centre, pharmacokinetic and pharmacodynamic interaction studies. Participants and methods: Twenty-seven healthy women (age 20-55 years) completed Study I, with a duration of 64 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 61 (third cycle day 6), and oral tazarotene 1.1 mg was co administered daily from study day 34 (second cycle day 7) to day 61. Twenty-nine healthy women (age 20-44 years) completed Study II, with a duration of 75 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 74 (third cycle day 19), and oral tazarotene 6mg was coadministered daily from study day 48 (second cycle day 21) to day 74. In both studies, the pharmacokinetics of tazarotenic acid on study day 61 (third cycle day 6) were evaluated from plasma tazarotenic acid concentrations. Pharmacokinetic parameters of plasma norethindrone and ethinylestradiol were compared before and after tazarotene administration (cycle day 6 of the second and third cycles, respectively). Serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were compared before and after tazarotene administration (cycle days 2, 4 and 6 of the second and third cycles, respectively). In Study II, serum progesterone concentrations were also determined on cycle days 18 and 20 of the second and third cycles. Tazarotenic acid was determined by liquid chromatography-tandem mass spectrometry. Ethinylestradiol and norethindrone were determined by gas chromatography-mass spectrometry. LH and FSH were assayed by microp article enzyme immunoas say in Study I and by double-antibody radioimmunoassay in Study IT. Progesterone was determined by solid-phase radioimmunoassay. Results: In Study I (tazarotene 1.1 mg), the area under the plasma concentration-time curve from zero to 24 hours (AUC24) and the peak concentration in plasma (Cmax) for tazarotenic acid were 121 ± 27 μg • h/L and 28.9 ± 9.4 μg/L (mean ± SD), respectively. In Study II (tazarotene 6mg), AUC24 and Cmax for tazarotenic acid were 379 ± 78 μg • h/L and 111 ± 37 μg/L (mean ± SD), respectively. In both studies, for both norethindrone and ethinylestradiol, the 90% CIs of AUC24 and Cmax on cycle day 6 before and after tazarotene administration were within the 80-125% boundary. In Study I, the 90% CIs of serum FSH and LH concentrations on cycle day 4 were within the 80-125% boundary. FSH and LH concentrations on cycle day 6 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean FSH and LH serum concentrations on cycle day 6 of the third cycle were lower than those of the second cycle. In Study II, the 90% CIs of serum FSH, LH and progesterone concentrations were all within the 80-125% boundary, except for LH on cycle day 2. LH concentrations on cycle day 2 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean serum LH concentration on cycle day 2 of the third cycle was lower than that of the second cycle. Conclusions: Oral tazarotene up to 6mg once daily does not affect the pharmacokinetics and efficacy of Ortho-Novum® 1/35. [ABSTRACT FROM AUTHOR]