L-DOPA, absorption

There are problems as well in the absorption of certain drugs in the presence of specific food components. L-Dopa absorption may be inhibited in the presence of certain amino acids formed from the digestion of proteins [43], The absorption of tetracycline is reduced by calcium salts present in dairy foods and by several other cations, including magnesium and aluminum [115-117], which are often present in antacid preparations. In addition, iron and zinc have been shown to reduce tetracycline absorption [118], Figure 17 illustrates several of these interactions. These cations react with tetracycline to form a water-in-soluble and nonabsorbable complex. Obviously, these offending materials should not be co-administered with tetracycline antibiotics. 

Tamai, I., et al. Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepTl. J. Pharm. Sci. 1998, 87, 1542-1546. 

A thorough discussion of the mechanisms of absorption is provided in Chapter 4. Water-soluble vitamins (B2, B12, and C) and other nutrients (e.g., monosaccharides, amino acids) are absorbed by specialized mechanisms. With the exception of a number of antimetabolites used in cancer chemotherapy, L-dopa, and certain antibiotics (e.g., aminopenicillins, aminoceph-alosporins), virtually all drugs are absorbed in humans by a passive diffusion mechanism. Passive diffusion indicates that the transfer of a compound from an aqueous phase through a membrane may be described by physicochemical laws and by the properties of the membrane. The membrane itself is passive in that it does not partake in the transfer process but acts as a simple barrier to diffusion. The driving force for diffusion across the membrane is the concentration gradient (more correctly, the activity gradient) of the compound across that membrane. This mechanism of... 

L Rivera-Calimlim, CA Dujovne, JP Morgan, L Lasagna, JR Bianchine. Absorption and metabolism of L-dopa by the human stomach. Eur J Clin Invest 1 313-320, 1971. 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

AJ Repta. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res 6(6) 501-505, 1989. 

Shindo, H., T. Komai, and K. Kawai. Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenyl-alanine (DOPA). V. Mechanism of intestinal absorption of D- and L-DOPA-14C in rats. Chem. Pharm. Bull. 1973, 21, 2031-2038. 

Bai, J. P. F., pGlu-L-Dopa-Pro a tripeptider prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversation, Pharm. Res. 1995, 12, 1101-1104. 

Some of the more interesting examples of nutrient - nonnutrient interactions include some of the compounds that are analogs of nutrients. Mattson et al (16) found that cholesterol absorption decreased when various plant sterols were added to the diets of rats. A number of plant amino acids are not ordinarily required by herbivores and are usually not incorporated into proteins. For example, the structure of 3,4-dihydroxyphenyl-alanlne (L-dopa) is similar to that of tyrosine. L-Dopa may play a role in favism (17), as well as having a number of other deleterious effects (18, 19, 20). Essential amino acids themselves can be deleterious if they are ingested in excessive quantities or if they are not in balance with other amino acids... 

HBS Hydrodynamically balanced system. A CR oral dosage form (capsule or tablet), which is designed to prolong the residence time within the stomach. Increased time for dissolution, prolonged absorption phase, and improved pharmacokinetic profile. Madopar HBS or Prolopa HBS (L-dopa + Benserazide) Vahelease (diazepam). 

L-Dopa is a prodrug of dopamine and is known as the drug of choice for the treatment of Parkinson s disease. L-Dopa has a narrow absorption window and is actively absorbed from the upper part of the small intestine. The large fluctuations in L-Dopa plasma concentration cause severe side effects. Hence, there is a PK rationale to elevate the extent of absorption while minimizing the maximum plasma concentration (Cmax) obtained, following oral administration of a sustained release (SR) formulation of L-Dopa. 

A recently developed unfolding GRDF formulation of L-Dopa showed, in a Beagle dogs model, a remarkable extension in the length of the absorption phase in comparison to non-GRDF, which led to flatter plasma concentration profile as shown in Fig. 1... 

These results are important in the development of a GRDF to achieve a delicate interplay in PK factors, prolonged absorption, and sustained blood levels for a compound that has a narrow absorption window owing to active transport and a steep pharmacodynamic profile and is suspected to first-pass metabolism. Based on these results, a new expandable GRDF of l-dopa, with different rigid polymeric matrices, was evaluated in healthy volunteers compared to SR formulation (Sinemit CR) (Fig. 2).t l... 

For most of the drugs, a better delivery system would significantly minimize the fluctuations in blood levels and consequently improve the therapeutic benefit of the drug as well as reduce its concentration-dependent adverse effect. This feature is of special importance for drugs with relatively narrow therapeutic index and narrow absorption window (e.g. L-Dopa). While the... 

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