The purpose of the present review article is to update the information regarding pharmacokinetics of drugs in patients with
heart failure that has accumulated since the last review article published in 1988 in Clinical Pharmacokinetics. Since this last review, our understanding of the pathophysiology of
heart failure has changed from the cardio-renal model to the neuro-humoral model, and the pharmacologic approach to treatment of
heart failure has been shifted from inotropic agents to those acting on the renin-angiotensin-aldosterone system. The pharmacologic agents now used for
heart failure include many important classes of drugs, such as
ACE inhibitors,
angiotensin receptor blockers (antagonists) (ARBs), and
mineralocorticoid receptor antagonists. In Part 1 of this review, we summarized the pharmacokinetic properties of relevant drugs administered intravenously. In Part 2, the present article, we describe pharmacokinetics of drugs following
oral administration. For this purpose we conducted a systematic search of literature using MEDLINE, EMBASE, and Japan Centra Revuo Medicina (in Japanese). We retrieved a total of 110 relevant publications for 49 drugs and updated the information for ten drugs and provided new information for 31 drugs. We recognized that the pharmacokinetic data were obtained primarily from stable
heart failure patients with moderate severity [New York Heart Association (NYHA) class II or III]. In addition, most patients were classified as
heart failure with reduced ejection fraction. Furthermore, because most of the studies retrieved had no comparative groups of healthy subjects or patients without
heart failure, historical controls from previous studies were used for comparisons. In Part 2, we also discuss the pharmacokinetics of active metabolites as well as parent drugs, because many drugs given by
oral administration for the treatment of
heart failure are
prodrugs (e.g.,
ACE inhibitors and ARBs). The pharmacokinetic changes of drugs in patients with
heart failure are discussed in the light of a physiologically based pharmacokinetic model. In addition, we discuss the effects of intestinal tissue
heart failure-associated
edema on
drug absorption as it relates to the
biopharmaceutical classification system, particularly for drugs demonstrating reduced systemic exposure as measured by the area under the plasma concentration-time curve after
oral administration (AUCpo) in patients with
heart failure as compared with healthy subjects. After review of the available data, it was seen that among patients with asymptomatic or compensated chronic
heart failure there seemed to be no or minimal alterations in the maximum concentration (C max) and AUCpo of the included drugs, unless there was concurrent liver and/or renal dysfunction. In contrast, the AUCpo of at least 14 drugs (
captopril,
cilazaprilat,
enalapril/
enalaprilat,
perindopril,
carvedilol,
candesartan,
pilsicainide,
felodipine,
furosemide,
enoximone,
milrinone,
flosequinan,
molsidomine, and
ibopamine) were suspected or documented to increase after
oral administration by 50% or more in patients with symptomatic or decompensated
heart failure.