Codeine biotransformation

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Morphine and codeine are both isolated from opium. Codeine (Schedule II), less potent that morphine, is biotransformed into morphine in the body and then further metabolized. 

Codeine, when incubated with the livers of several mammalian species, is converted to morphine and formaldehyde. The biotransformation products identified in the urine following the administration of codeine include morphine, norcodeine, and free and bound codeine. 

With respect to treatment, depending on the particular biotransformation pattern and the activity of the metabolites, several therapeutic approaches are evident. For example, EMs (93 percent of the Caucasian population) could receive an inhibitor as part of a therapeutic regimen. Such inhibition will alter the kinetics, toxicity, drug-reinforcing properties, and physical dependence liability of some drugs of abuse (e g., hydrocodone, oxycodone, codeine) and make the drug less pharmacologically attractive. 

Jairaj M, Watson DG, Grant MH, Gray AI, SkeUem GG. Comparative biotransformation of morphine, codeine and pholcodine in rat hepatocytes identification of a novel metabolite of pholcodine. Xenobiotica 2002 32 1093-1107. 

Production can be increased by addition of precursors to the culture media, in which cases the precursors are not metabolized in the medium and, after uptake, appear in the right compartment of the plant cell. For C. roseus cultures, for example, it was found that increased indole alkaloid production was obtained after feeding with L-tryptophan, tryptamine, secologanin, loganin, loganic acid, or shikimic acid (20). Cell cultures have also been used for biotransformations, for example, the conversion of (-)-codeinone to (-)-codeine in Papaver somniferum cultures (100). For the tropane alkaloids a large number of precursor feeding and biotransformation studies with cultures of various solanaceous plants have been performed (see below). 

The first reported biotransformation by means of cell cultures of P. somniferum was the conversion of thebaine to codeine (453). As P. som-nifemm cell cultures only produced alkaloids derived from (5)-reticuline (e.g., sanguinarine. Fig. 9) but none of the alkaloids derived from (/ )-reticuline, Furuya et al. 461) administered (R,S)-reticuline to the cell suspension cultures. After 3 days the alkaloids were isolated. Two alkaloids derived from (5)-reticuline were identified cheilathifoline and scoulerine. A third alkaloid isolated was identified as pure (/ )-reticuline. Thebaine, morphine, and codeine were not metabolized by these cell cultures. However, the cells were capable of stereospecifically reducing codeinone to codeine. Tam et al. 462) also found the same bioconversion. Furthermore, the conversion of thebaine to neopine was reported. Codeine, neopine, papaverine, and D,L-laudanosoline were not metabolized. Enzymatic reduction of codeinone to codeine was also achieved with cell-free preparations of whole plants of both P. somniferum and P. bracteatum 464). Yeoman and co-workers 108,465) reported the use of in reticulate polyurethane immobilized P. somniferum cells for this bioconversion. 

Furuya et al. (468) reported the immobilization of P. somniferum cells in calcium alginate. CeUs remained viable for 6 months after immobilization. The cells were used in shake flasks and column bioreactors for the biotransformation of codeinone to codeine. The immobilized cells had a higher biotransformation ratio (70%) than suspended cells (61%). Most of the codeine formed was excreted into the medium (88%). The column bioreactor had a lower biotransformation ratio (42%). The cells in the bioreactor operated at 20°C and an aeration rate of 3.75 vvm (volume gas/volume broth/min) remained catalytically active for 30 days. In a more detailed study on the influence of substrate transport in immobilized cells, it was concluded that limitation of oxygen inside the beads caused deactivation of the cells. However, the reaction rate of the system was not affected by the limitation of oxygen transfer (469). Immobilization of P. 

The vast majority of biosynthetic reactions are enzyme-catalyzed and, therefore, show considerable stereoselectivity and substrate specificity. In general, stereoselectivity is more important than substrate specificity, and many unnatural morphinan derivatives have been produced biosynthetically (Kirby et al. 1972, Brochmann-Hanssen and Okamoto 1980, Brochmann-Hanssen and Cheng 1982, 1984, Brochmann-Hanssen et al. 1982). The oxidative coupling of reticuline to salutaridine as well as the succeeding biotransformations are not very substrate specific. Several reticuline analogues have been converted to the corresponding morphine and codeine... 

Coutts IGC, Hamblin MR, Tinley EJ (1979) The enzymatic oxidation of phenolic tetrahydroiso-quinoline-1-carboxylic acids. J Chem Soc Perkin Trans 1 2744-2750 Davis VE, Cashaw JL, McMurtrey KD, Ruchirawat S, Nimit Y (1982) Metabolism of tetrahydro-isoquinolines and related alkaloids. In Bloom F, Barchas J, Sandler M, Usdin E (eds) Beta-carbolines and tetrahydroisoquinolines. Liss, New York, p 99 Furuya T, Nakano M, Yoshikawa T (1978) Biotransformation of (RS)-reticuline and morphinan alkaloids by cell cultures of Papaver somniferum. Phytochemistry 17 891-893 Gates M (1953) Conversion of codeinone to codeine. J Am Chem Soc 75 4340-4341 Graves JMH, Smith WK (1967) Transformation of pregnenolone and progesterone by cultured plant cells. Nature (London) 214 124 8-1249... 

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