Metabolites alkaloid drug

LC-MS/MS Approaches to the Identification/Structural Elucidation of Alkaloid Drug Metabolites... 

To avoid the expensive use of deuterated solvents for H/D exchange experiments, Tolonen et al. [21] have described the postcolumn infusion of D2O to facilitate the LC-MS detection and identification of labile protons in a column eluant. Whilst acknowledging the potential limitations with respect to a reduced level of exchange, and hence sensitivity, compared to the use of deuterated mobile-phase solvents, they optimized the column effluent flow rate (via a splitting connector) with the infused D2O flow rate to enable the very useful determination of up to four labile protons. The method was exemplified by the differentiation of hydroxylated metabolites of the alkaloidal drugs imipramine and omeprazole (Figure 13.5) from the N-oxide and sulfone metabolites, respectively [21]. This was a differentiation that could not be achieved by high-resolution mass measurements. 

Lin G, Cui Y, Hawes EM (1998) Microsomal formation of a pyrrolic alcohol glutathione conjugate of Clivoiine firm evidence for the formation of a pyrrolic metabolite of an otonecine-type pyrrolizidine alkaloids. Drug Metab Dispos 26 181-184... 

Thermospray ionization was especially applied between 1987 and 1992 in combination with LC-MS for a wide variety of compound classes, e.g. pesticides and herbicides, drugs and metabolites, alkaloids, glycosides and several other natural products, as well as peptides. 

Saponins are glycosylated secondary metabolites that are widely distributed in the Plant Kingdom.3,4 They are a diverse and chemically complex family of compounds that can be divided into three major groups depending on the structure of the aglycone, which may be a steroid, a steroidal alkaloid, or a triterpenoid. These molecules have been proposed to contribute to plant defense.3 6 Saponins are also exploited as drugs and medicines and for a variety of other purposes.4 Despite the considerable commercial interest in this important group of natural products, little is known about their biosynthesis. This is due in part to the complexity of the molecules, and also to the lack of pathway intermediates for biochemical studies. 

Analysis of tropane alkaloids in biological fluids has been developed mostly for cocaine and metabolites. Indeed, it is well recognized that cocaine remains one of the most widely consumed drugs of abuse worldwide. Generally, reversed phase liquid chromatography coupled with UV-VIS detection is employed for these analyses. 

Several note vorthy halogenated terrestrial alkaloids are known, with epibatidine (104) at the top of the list [88]. This apparent frog Epipedobates tricolor) metabolite has powerful analgesic activity [89] and an intensive search is underway for a clinically useful drug [90]. A few chlorinated plant alkaloids have also been discovered. Romucosine F (lOS) is present in Annora purpurea, a South American bushy tree [91], and the closely related romucosine B (106) is found in the stems of RolUnia mucosa [92]. The furoquinoline alkaloid chlorodesnkolbisine (107) was isolated from the African folk medicine plant Teclea nobilis [93]. The authors of this latter study provide convincing evidence that 107 is not an isolation artifact (e.g. from the corresponding epoxide with HCl). 

There are many examples in the literature for applications of LC-NMR in the pharmaceutical industry. In the area of natural products, LC-NMR has been applied to screen plant constituents from crude extracts [54,57,67,68] and to analyze plant and marine alkaloids [69-72], flavonoids [73], sesquiterpene lactones [74,75], saponins [58,76], vitamin E homologues [77], and antifungal and bacterial constituents [56,78,79] as examples. In the field of drug metabolism, LC-NMR has been extensively applied for the identihcation of metabolites [42, 80-88] and even polar [89] or unstable metabolites [43]. And hnally, LC-NMR has been used for areas such degradation products [90-93], drug impurities [94-102], drug discovery [103,104], and food analysis [105-107]. 

Cocaine HCl is an alkaloid derived from the leaves of the South American coca plant. The free base alkaloid, made by extraction from cocaine HCl, is relatively insoluble in water, but dissolves in a variety of organic solvents. There has been a dramatic increase in the use of cocaine free base, which is most commonly known by its street name "crack". Since free base is not destroyed by heating, but rather vaporizes, it can be smoked and inhaled [129]. This provides speedy absorption from the respiratory tract inducing a short-lived but rapid euphoria. The free base is also well absorbed by nasal, vaginal, gastrointestinal and subhngual mucous membranes. Cocaine can be injected intravenously, intramuscularly or subcutaneously. Crack is often combined with heroin or other drugs of abuse and taken intravenously [128]. Cocaine is detoxified by cholinesterases and cocaine or its metabolites may be present in the urine for one to two days after use. 

The MBl for LC-MS was used in a wide variety of applications, including the analysis of drugs and their metabolites, pesticides, steroids, alkaloids, polycychc aromatic hydrocarbons, and others [26], One example is briefly discussed here. 

---