Devarakonda Rama Krishna

Extrahepatic Metabolism of Drugs in Humans

SummaryAlthough the liver plays the major role in drug metabolism [e.g. by oxidative cytochrome P450 (CYP)-dependent phase I and conjugation or phase II reactions], drug metabolising enzymes are also present at other sites. Depending on the particular drug and enzymes involved, these extrahepatic organs and/or tissues can contribute to the elimination of drugs and, thus, should be considered in any discussion of drug disposition.By the use of relatively new techniques in molecular biology, e.g. immunoblotting with antibodies directed to various CYP isoenzymes, the tissue and organ distribution of these drug metabolising enzymes can be determined. In addition, microsomal and cytosolic enzyme activity and capacity can be directly assessed in vitro by incubation of the enzymes with the drugs of interest. Both approaches have demonstrated the presence of 3 CYP families at different extrahepatic sites, such as the mucosa of the gastrointestinal tract, kidney, lung, brain or skin. Enzymes including epoxide hydrolases, hydrolysing enzymes, glutathione S-transferases, UDP-glucuronosyltransferases, sulphotransferases, N-acetyltransferases, and methyltransferases are discussed.Indirect evidence of extrahepatic drug metabolism can be generated from pharmacokinetic studies whenever total body clearance exceeds liver blood flow, or when severe liver dysfunction or anhepatic conditions do not affect metabolic clearance. Indeed, extrahepatic metabolism has been demonstrated for numerous drugs. Therefore, the metabolic profile and sites of enzymatic reactions for each drug should be determined.

Detection of desmethyldiazepam and diazepam in brain of different species and plants

Recent data suggest that desmethyldiazepam (DD), a major metabolite of several benzodiazepines (BZD), might be of natural origin. Therefore we tried to quantify DD and diazepam (D) in animals during maturation (e.g. hen, chicken, eggs), in brain of species at different evolutionary stages e.g. salmon, frog, monitor/reptile, rat, cat, dog, deer, bovine) including newborn and adult humans. Since low concentrations of DD (range 0.01-0.04 ng/g wet wt) and D (range 0.005-0.02 ng/g) could be measured in different species by sensitive and specific mass spectrometry (GC-MS), we analysed also several plants (e.g. maize corn, lentils, potatoes, soybeans, rice, mushrooms). Again, DD and D could be detected in low amounts (0.005-0.05 ng/g) in some plant products. This would suggest that DD and D might be of natural origin and incorporated via the foodchain into the animal and human body. The biological role or clinical relevance of these intriguing findings need still to be elucidated.

Newer H2-receptor antagonists: clinical pharmacokinetics and drug interaction potential

SummarySince H2-receptor antagonists are widely and successfully used in the treatment of peptic ulcer, several alternatives to the standard agents cimetidine and ranitidine have been developed. Promising ‘new’ candidates might be famotidine and nizatidine. For proper selection of the appropriate drug, its pharmacokinetic properties and interaction potential should be known. All ‘old’ and ‘new’ H2-receptor blockers are eliminated relatively rapidly (t½ ranges from 1.5 to 4 hours), mainly by the renal route (glomerular filtration and tubular secretion). They exhibit a linear disposition and their distribution is similar. Absorption is most complete for nizatidine, whereas famotidine demonstrates the lowest effective plasma concentrations. Since etintidine shares the same imidazole ring structure as cimetidine, it can also impair oxidative drug metabolism in the liver. In this respect, the non-interacting famotidine and nizatidine (like ranitidine) offer a definite advantage. Based on their very similar pharmacokinetic and interaction profiles, these 2 H2-receptor antagonists might be regarded as alternatives to the older drugs in this group, and at least some economic benefits might result from the competition they will provide.

Newer H2-Receptor Antagonists

SummarySince H2-receptor antagonists are widely and successfully used in the treatment of peptic ulcer, several alternatives to the standard agents cimetidine and ranitidine have been developed. Promising ‘new’ candidates might be famotidine and nizatidine. For proper selection of the appropriate drug, its pharmacokinetic properties and interaction potential should be known. All ‘old’ and ‘new’ H2-receptor blockers are eliminated relatively rapidly (t½ ranges from 1.5 to 4 hours), mainly by the renal route (glomerular filtration and tubular secretion). They exhibit a linear disposition and their distribution is similar. Absorption is most complete for nizatidine, whereas famotidine demonstrates the lowest effective plasma concentrations. Since etintidine shares the same imidazole ring structure as cimetidine, it can also impair oxidative drug metabolism in the liver. In this respect, the non-interacting famotidine and nizatidine (like ranitidine) offer a definite advantage. Based on their very similar pharmacokinetic and interaction profiles, these 2 H2-receptor antagonists might be regarded as alternatives to the older drugs in this group, and at least some economic benefits might result from the competition they will provide.

Introduction and definitions

To develop the best practices and recommendations for instruction in digital citizenship, Internet safety, and media literacy, Substitute Senate Bill 6273 (http://app.leg.wa.gov/billsummary?BillNumber=6273&Year=2015) directed the Office of Superintendent of Public Instruction (OSPI) to convene and consult with an advisory committee, which was to include representatives from the Washington State School Directors Association (WSSDA); experts in digital citizenship, Internet safety, and media literacy; teacher-librarians; and other stakeholders including educators, administrators, and representatives from parent associations.

Newer H 2 -Receptor Antagonists

SummarySince H2-receptor antagonists are widely and successfully used in the treatment of peptic ulcer, several alternatives to the standard agents cimetidine and ranitidine have been developed. Promising ‘new’ candidates might be famotidine and nizatidine. For proper selection of the appropriate drug, its pharmacokinetic properties and interaction potential should be known. All ‘old’ and ‘new’ H2-receptor blockers are eliminated relatively rapidly (t½ ranges from 1.5 to 4 hours), mainly by the renal route (glomerular filtration and tubular secretion). They exhibit a linear disposition and their distribution is similar. Absorption is most complete for nizatidine, whereas famotidine demonstrates the lowest effective plasma concentrations. Since etintidine shares the same imidazole ring structure as cimetidine, it can also impair oxidative drug metabolism in the liver. In this respect, the non-interacting famotidine and nizatidine (like ranitidine) offer a definite advantage. Based on their very similar pharmacokinetic and interaction profiles, these 2 H2-receptor antagonists might be regarded as alternatives to the older drugs in this group, and at least some economic benefits might result from the competition they will provide.