Literature data on compounds both well- and poorly-absorbed in humans were used to build a statistical pattern recognition model of passive intestinal absorption. Robust outlier detection was utilized to analyze the well-absorbed compounds, some of which were intermingled with the poorly-absorbed compounds in the model space. Outliers were identified as being actively transported. The descriptors chosen for inclusion in the model were PSA and AlogP98, based on consideration of the physical processes involved in membrane permeability and the interrelationships and redundancies between available descriptors. These descriptors are quite straightforward for a medicinal chemist to interpret, enhancing the utility of the model. Molecular weight, while often used in passive absorption models, was shown to be superfluous, as it is already a component of both PSA and AlogP98. Extensive validation of the model on hundreds of known orally delivered drugs, “drug-like” molecules, and Pharmacopeia, Inc. compounds, whic...

Prediction of drug absorption using multivariate statistics.

Recent advances in the field of carrier-mediated intestinal absorption of of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids and several water-soluble vitamins across brush-border and basolateral membranes are summarized. An understanding of the molecular and functional characteristics of the intestinal membrane transporters will be helpful in the utilization of these transporters for the enhanced oral delivery of poorly absorbed drugs. Some successful examples of the synthesis of prodrugs recognized by the targeted transporters are described. Functional expression of the multidrug resistance gene product, P-glycoprotein, as a primary active transporter in the intestinal brush-border membrane leads to net secretion of some drugs such as anticancer agents in the blood-to-luminal direction, serving as a secretory detoxifying mechanism and as a part of the absorption barrier in the intestine.

Carrier-Mediated Intestinal Transport of Drugs

Captopril is an orally active inhibitor of angiotensin-converting enzyme (ACE) and has been widely studied in the treatment of patients with mild to moderate essential hypertension, severe hypertension not responsive to conventional diuretic/beta-adrenoceptor blocker/vasodilator regimens, and patients with chronic congestive heart failure refractory to treatment with a diuretic and digitalis. In patients with mild or moderate essential hypertension, titrated low doses of captopril used alone or in conjunction with a diuretic are similar in efficacy to usual doses of hydrochlorothiazide, chlorthalidone, or beta-adrenoceptor blocking drugs, as well as to the other ACE inhibitors. In addition, captopril improved well-being to a greater extent than methyldopa or propranolol in a study designed specifically to determine the effect of treatment on the quality of life of patients with mild or moderate essential hypertension. The earlier demonstrated efficacy of captopril, used with a diuretic and often also with a beta-adrenoceptor blocking drug, in the treatment of severe hypertension refractory to conventional 'triple therapy' has been confirmed in more recent trials which illustrate the generally marked antihypertensive effect of captopril-containing regimens in such patients. Results of initial trials in patients with scleroderma are promising, with control of hypertension and stabilization of renal function in these patients when treated at an early stage of the disease. Several comparative and long term trials of captopril in patients with chronic congestive heart failure refractory to treatment with a diuretic/digitalis regimen clearly demonstrate that initial haemodynamic improvement is maintained and correlates with clinical benefit. A tendency for overall clinical response to captopril to be better than the response to prazosin, hydralazine, nisoldipine or enalapril has been reported. Results of a multicentre comparison with digoxin and placebo indicate that captopril is a suitable alternative to digoxin in patients with mild to moderate heart failure who are receiving maintenance diuretic therapy. The tolerability of captopril has now been studied in many thousands of patients involved in formalized trials and the early impression of poor tolerability can no longer be justified. The use of generally lower dosages of captopril in patients with normal or slightly impaired renal function has resulted in a generally low incidence of rash (0.5 to 4%), dysgeusia (0.1 to 3%), proteinuria (0.5%), neutropenia (0.3% during first 3 months) and symptomatic hypotension (0.1 to 3%). Cough is an infrequent but troublesome effect resulting from ACE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)

Captopril. An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure.

The dopamine depletion that is characteristic of Parkinson's disease has been hypothesized to result from the combination of environmentally induced subclinical damage to the substantia nigra and the age-related loss of additional nigral neurons. Essential to this hypothesis is the existence of deteriorating function in the nigrostriatal pathway with advancing age. The present study was undertaken with [18F]6-fluoro-L-dopa and positron emission tomography to determine in vivo the effects of age on the nigrostriatal pathway in a series of 10 asymptomatic subjects (age range, 22-80 years; mean, 49.8 years). A graphical approach was used in the analysis of multiple-time tracer-uptake data to establish the presence of a compartment with unidirectional uptake and to calculate the rate constant, K, for uptake of [18F]6-fluoro-L-dopa from blood to striatum during steady-state, an index of the functional integrity of nigrostriatal nerve endings. There was a significant linear relationship between K and age (r = 0.80, p less than 0.005) with a decrease of 53.3% over the age range studied. These results demonstrate the application of a unidirectional transfer model to the analysis of [18F]6-fluoro-L-dopa and positron emission tomography data and provide in vivo confirmation of an age-related impairment of nigrostriatal function.

Nigrostriatal function in humans studied with positron emission tomography

Metal complexes of aromatic amine n-oxides

Infrared spectra of substituted pyridine 1-oxides with various kinds of substituent mainly at 3- or 4-position were determined. Their N-O stretching frequencies (strong absorption in the region of 1200 and 1300cm-1) were found to be correlated with the nature of a substituent, and a linear relation between these frequencies and σ-values of the substituents was pointed out. The ring C-H out-of-plane bending frequencies of these compounds showed a regular shift from those of the parent pyridines, shifting always to a higher frequency in 2- and 4-substituted derivatives, and always to a lower frequency in 3-substituted derivatives. Absorptions in the regions of 900∼1200cm-1 and 1450∼1630cm-1 were also correlated with the structure. From a comparison of the frequency shift in a characteristic vibration of the ring substituent, the σ-values of 0.25 and 1.18 were respectively obtained for 4- and 3-positions of pyridine 1-oxides. All these points were discussed in terms of an electronic effect of the N-oxide function.

Studies on the Infrared Spectra of Heterocyclic Compounds. V. Infrared Spectra of Substituted Pyridine 1-Oxides.

https://www.jstage.jst.go.jp/article/jnsv1973/20/3/20_3_163/_pdf

Active transport of thiamine from rat small intestine.

The infrared spectra of pyrazine, its eight mono-substituted derivatives, and their ten N-oxide derivatives were analyzed. Their characteristic N-O streching frequencies (a strong absorption in the region of 1250 and 1350 cm-1) were found to be correlated to the nature of a substituent present and the linear relationship between the N-O frequency and the σ-value of a substituent in substituted pyridine N-oxides could be extended to that in substituted pyrazine N-oxides by applying the σ-value of ring nitrogen (0.93) and the N-oxide group (0.25) toward 4-position of pyridine for mono- and di-N-oxides, respectively. The considerably higher frequency shift of the N-O frequency was shown to be characteristic for the methyl group at β-position with respect to the N-oxide group. Ring and ring CH vibrations were discussed on the basis of the correlations found in the pyridine ring system. The splitting of the carbonyl stretching frequency of ester group adjacent to ring nitrogen was pointed out and discussed. The infrared spectra of pyrimidine N-oxide and its eight derivatives were also examined and discussed in comparison with the above results.

Hideyo Shindo

Papers

Studies on the Infrared Spectra of Heterocyclic Compounds. V. Infrared Spectra of Substituted Pyridine 1-Oxides.

Active transport of thiamine from rat small intestine.

Studies on the Infrared Spectra of Heterocyclic Compound. VIII. Infrared Spectra of Substituted Pyrazines and their N-Oxides

Studies on the Infrared Spectra of Heterocyclic Compounds. VII. Hydrogen-Bond Effect on Pyridine 1-Oxide and its Derivatives

Urinary metabolites of 1-(3-Mercapto-2-D-methyl-1-oxopropyl)-L-proline(SQ-14225),a new antihypertensive agent, in rats and dogs.