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.

1 The disposition of two angiotensin converting-enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK-421), which requires in vivo esterolysis to yield active inhibitor (MK-422). The other was a lysine analogue of MK-422 (MK-521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5-1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK-422), absorption was at least 61%. Bioactivation appeared to be largely post-absorptive. From the ratio of MK-422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK-521 was absorbed more slowly, reaching peak serum concentrations 6-8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK-422) was 94%. Recovery of MK-521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.

Enalapril maleate and a lysine analogue (MK-521): disposition in man.

PURPOSE The aim of the study was the prediction of human intestinal permeability and fraction absorbed of oral dose using single-pass intestinal perfusion technique (SPIP) in rats. METHODS Permeability coefficients in anaesthetized rats were determined for 14 compounds. Drug solution in phosphate buffered saline (PBS) was perfused through a ingle-pass intestinal perfusion (SPIP) with flow rate of 0.21 ml/min and samples were taken from outlet tubing at different time points up to 90 min. Phenol red was used as a non-absorbable marker to correct water flux through the segment. Drug concentrations in samples were determined using HPLC and permeability coefficients (Peff) were calculated. RESULTS The examined compounds demonstrated approximately 12.5 fold difference in magnitude for rat permeability coefficients among themselves. These values were compared with published data for human intestinal permeability, and a strong correlation was found between Peff (rat) and Peff (human); (Peff (human) = 11.04 Peff (rat) - 0.0003; R2= 0.93, P<0.0001). Subsequently the fraction dose absorbed in human (Fa) was estimated and predicted after oral dosing considering Fa(human)=1-e - 38450Peff(rat) (R2= 0.91, P<0.0001). CONCLUSIONS Considering the high correlation of rat Peff values with those of human we conclude that the SPIP could be utilized with precision to predict the human intestinal permeability. It may also be used as a reliable technique to predict the fraction of dose absorbed following oral administration of drug in solution or regular release dosage form in human.

Predicting human intestinal permeability using single-pass intestinal perfusion in rat.

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

Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). V. Mechanism of intestinal absorption of D- and L-DOPA-14C in rats.

The metabolic pathway of SQ 14225 (Captopril) and the mechanism of the mixed disulfide formation with endogenous sulfhydryl compounds were studied in in vitro cell free systems. In the rat liver 9000×g supernatants, SQ 14225-14C was metabolized to one major metabolite, glutathione-SQ 14225 mixed disulfide (GSSQ), and two minor metabolites including SQ 14551, a symmetrical disulfide of SQ 14225. The formation of GSSQ was markedly accelerated by the addition of oxidized glutathione (GSSG), but not affected by the addition of reduced glutathione (GSH), indicating that GSSQ was formed by the thiol-disulfide interchange between SQ 14225 and GSSG. Although the thiol-disulfide interchange was also observed between SQ 14225 and L-cystine, L-homocystine and SQ 14551 as well as GSSG, only the formation of GSSQ was a rapid reaction and markedly decreased by heat treatment of the liver 9000×g supernatants. These findings demonstrate that the formation of GSSQ is catalyzed by a GSSG specific enzyme which is supposed to be thioltransferase (Glutathione : Disulfide Oxidoreductase). Although GSSQ was stable in the rat liver 9000×g supernatants, it was rapidly hydrolyzed to cysteine-SQ 14225 mixed disulfide (CySSQ) in the rat kidney 9000×g supernatants. A specific inhibitor of γ-glutamyltranspeptidase, anthglutin, inhibited the hydrolysis. GSSQ-14C administered to a beagle dog was excreted into the urine in the form of CySSQ. Thus, it was speculated that CySSQ excreted into the urine as a major metabolite of SQ 14225 was derived from GSSQ formed in the liver followed by hydrolysis in the kidney.

In vitro studies on the metabolic pathway of sq 14225 (captopril) and mechanism of mixed disulfide formation

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Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). 3. Absorption, distribution and excretion of D- and L-DOPA-14C in rats following intravenous and oral administration.

The intestinal absorption and the site for hydrolysis of pivampicillin were compared with those of ampicillin by in situ ligated loop method in rats, using the radioactive compounds labeled at the phenylglycyl and the oxymethylene moieties. It was shown that pivampicillin is well absorbed from all parts of intestine, while ampicillin is absorbed from a more limited part of intestine. Pivampicillin was found to be rapidly transferred from the lumen into the intestinal wall as an intact ester and was hydrolyzed rapidly in the tissue. Ampicillin thus formed appeared to be transitorily accumulated in the tissue before being transferred into the portal venous blood gradually. Ampicillin was absorbed slowly without any accumulation in the intestinal wall. Microautoradiography of pivampicillin-14C in the intestine demonstrated that the radioactivity is accumulated in the epithelial cells in a high concentration. Histochemical and cytochemical detection of non-specific esterase revealed that a high activity is located specifically in the epithelial cells of villi and that the activity is localized in the membranes of endoplasmic reticulum as well as the cytoplasm, while there was almost no activity in the microvilli and terminal web region. It is considered therefore that pivampicillin is penetrated into the epithelial cells without any cleavage of the ester group and hydrolyzed by non-specific esterase in the apical cytoplasm of the cells. When the esterase activity was compared histochemically in rats, dogs and monkeys, it was found that the activity was extremely weak in dog intestine, providing an explanation for the fact that intact pivampicillin was detected in the portal venous blood only in dogs after oral administration. A possible relation between these results and the fact that a hepatic toxicity of pivampicillin was observed only in dogs among these animals was pointed out and discussed.

Kenji Kawai

Papers

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

Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). V. Mechanism of intestinal absorption of D- and L-DOPA-14C in rats.

In vitro studies on the metabolic pathway of sq 14225 (captopril) and mechanism of mixed disulfide formation

Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). 3. Absorption, distribution and excretion of D- and L-DOPA-14C in rats following intravenous and oral administration.

Studies on intestinal absorption of pivampicillin and species difference in the intestinal esterase activity