Enalapril, manufacture

In a study in 12 patients with hypertension taking enalapril20 mg daily, the addition of nicardipine 30 mg three times daily for 2 weeks did not alter the pharmacokinetics of enalapril. The manufacturer of spirapril briefly noted in a review that the concurrent use of spirapril and nicardipine increased spirapril plasma levels by about 25% and those of its active metabolite, spiraprilat, by about 45%. The bioavailability of nicardipine was reduced by 30%. It was assumed that the interaction took place at the absorption site. However, the changes were not considered clinically relevant. ... 

Other single-dose studies have shown that food had no statistically significant effect on the pharmacokinetics of lisinopril, or enalapril, and its active metabolite, enalaprilat. Similarly, food had minimal effects on the pharmacokinetics of cilazapril (AUC decreased by only 14%). Food caused small, but statistically significant increases in the time to reach maximum plasma levels of quinapril and its active metabolite. However, as the increase was less than 30 minutes this is not expected to alter the therapeutic effect. Likewise, the manufacturers of spirapril briefly mention in a review that food delayed its absorption by 1 hour, it did not affect the bioavailability of spirapril or spiraprilat, its active metabolite. Other manufacturers state that food had no effect on the absorption of fosinopril 11,12 ramipril, or trandolapril. ... 

Cimetidine did not appear to alter the pharmacokinetics or pharmacological effects of captopril or enalapril, or the pharmacokinetics of fosinopril or quinapril in studies in healthy subjects. The manufacturers of cilazapril say that no clinically significant interaction occurred with H2-receptor antagonists (not specifically named) and the manufacturers of moexipril, " ramipril, and trandolapril say that no important pharmacokinetic interaction occurred with cimetidine. The manufacturers of spirapril briefly note in a review that cimetidine did not alter the plasma concentrations of spirapril or its active metabolite spiraprilat. None of these pairs of drugs appears to interact to a clinically relevant extent, and no special precautions appear to be necessary. 

The manufacturer of spirapril briefly noted in a review that there was no relevant pharmacokinetic interaction between spirapril and diclofenac. Oxaprozin 1.2 g daily for 3 weeks did not affect the pharmacokinetics of enalapril 10 to 40 mg daily in 29 patients with hypertension. A brief mention is made in a review that, in healthy subjects, the pharmacokinetics of ramipril were unaffected by indometacin [dosage not stated] given for 3 days. ... 

The general importance of these interactions is uncertain. The isolated reports with enalapril suggest minor clinical relevance. The manufacturers of spirapril did not consider the modest pharmacokinetie ehanges to be clinically relevant. However, the manufacturers of imidapril state that rif-ampicin might reduce the antihypertensive efficaey of imidapril, but this awaits clinical assessment. 

Two kidney transplant patients on ciclosporin developed acute renal failure 10 to 42 days after starting to take enalapril 5 to 10 mg twice daily. Recovery was complete when the enalapril was stopped in one of the patients, and when both enalapril and ciclosporin were stopped in the other. The latter patient had no problems when the ciclosporin was restarted. Both recovered renal function after 10 to 30 days. Neither had any previous evidence of renal artery stenosis or chronic rejection, which are conditions known to predispose to renal failure during ACE inhibitor treatment. Two other patients appeared to tolerate concurrent use well. Two further kidney transplant patients developed acute renal failure when given enalapril. Neither had renal arterial stenosis or acute rejection. The manufacturer briefly mentions that transient oliguria was seen in a kidney transplant patient given ciclosporin and captopril. ... 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

Types of chiral processes amenable to scale-up Specific examples of the manufacture of chiral drugs Diltiazem Captopril Enalapril Naproxen... 

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