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Simonen et al. focused on cholesterol species and examined the association of desmosterol, cholestanol,
and lasosterol in serum and liver with liver histology in 110 obese patients (Kuopio Bariatric Surgery Study,
age 43.7 6 8.1 years, BMI 45.0 6 6.1 kg/m
2
). Serum desmosterol levels and desmosterol-cholesterol ratios
were higher in NASH patients but not in NAFL patients compared to obese subjects with normal liver histol-
ogy. Serum and hepatic desmosterol levels were strongly correlated, suggesting the existence of a common
regulatory mechanism. Serum and liver desmosterol levels were positively correlated with fat accumulation
and inflammation in the liver. Serum desmosterol levels were more highly correlated with cholesterol accu-
mulation in the liver than serum c holesterol levels
[28]. These studies suggest that the major hepatic lipid in
NAFLDareTAGorDAG,andthemorecholesteroldeposition could accelerate hepatic inflammation, lead-
ing N ASH.
I asked the next question is: “Is there any genetic background sharing NAFLD/NASH and atherosclerosis?”
The genetic variant (rs738409 C . G p. I148M) in patatin-like phospholipase domain containing 3 (PNPLA3) was
identified as a NAFLD gene in genome wide association study (GWAS). The PNPLA3 protein has lipase activity
toward triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. An allele in PNPLA3 (rs738409
C . G p. I148M) was relatively common variant and strongly associated with increased hepatic fat levels and
with hepatic inflammation
[29]. On the other hand, several GWASs on CAD and serum lipid have been per-
formed around 2008, however, PNPLA3 was detected neither in CAD nor in serum lipid
[30,31]. This might sug-
gest that genetic background cannot explain the linkage between NAFLD/NASH and CAD.
Tetratricopeptide repeat domain protein 39B (TTC39B) is one of GWAS genes originally identified as a HDL-
C-related gene
[31]. We have generated Ttc39b-knockdown and knockout mice and found that deficiency of
Ttc39B, which served as a scaffold protein between the nuclear receptor, liver X receptor (LXR), and ubiquitin
ligase, suppressed ubiquitination of LXR and stabilizes LXR. Interestingly, in Ttc39b-KO mice, cholesterol absorp-
tion and accumulation in the body were inhibited, and that the progression of atherosclerosis and NASH were
both suppressed
[32]. Although the expression of TTC39B in patients with NAFLD/NASH are still unknown,
these data suggested that LXR-cholesterol axis might be involved with the individuals with NASH and CVD.
Ekstedt et al. have reported that patients with NAFLD are at a higher risk of death due to cardiovascular and
liver-related diseases and the stage of liver fibrosis alone predicted both the overall and the disease-specific mor-
tality, whereas the NAFLD activity score failed to predict the overall mortality
[33]. Since then, therapeutic agents
against hepatic fibrosis have been vigorously challenged to develope.
Association between NAFLD/hepatic fibrosis and cardiac dysfunction
Importantly, it has been demonstrated that NAFLD or hepatic fibrosis might be associated with cardiac dys-
function, independently of atrherosclerosis. Lee et al. have published a study using echocardiography and [
18
F]-
fluorodeoxyglucose-positron emission tomography to determine whether myocardial dysfunction, myocardial
glucose uptake, and liver fibrosis were associated in 118 patients with NAFLD and 190 patients without NAFLD.
The results showed that NAFLD patients had an increased left ventricular myocardial weight index, left ventricu-
lar end-diastolic diameter, and left atrial volume index compared with nonNAFLD patients, suggesting that myo-
cardial remodeling is underway. Analysis using transient liver elastography (Fibroscan) showed that liver
fibrosis was significantly correlated with left ventricular diastolic dysfunction and impaired myocardial glucose
uptake. By using multivariate linear regression analysis, it was observed that left ventricular filling pressure
(E/e´), and reflecting diastolic dysfunction were independently associated with liver fibrosis. There was also a
significant association of E/e´ with the degree of HS
[34].
It has been also investigated whether the presense of hepatic fibrosis might have impact on exercise tolerance.
Canada et al. have performed cardiopulmonary exercise load testing and stress echocardiography on 36 subjects
(15 with NAFL and 21 with NASH) to examine the relationship between the degree of liver fibrosis, left ventricu-
lar diastolic capacity, and maximal oxygen uptake in patients with NAFLD. Importantly, NASH was associated
with lower maximal oxygen uptake (pVO
2
) compared to NAFL. As fibrosis progressed, peak VO
2
decreased and
stress E/e´ increased
[35].
Based on these findings, the stage of hepatic fibrosis has been implicated in not only atherosclerotic lesion for-
mation, but also left ventricular remodeling, left ventricular diastolic capacity, and exercise tolerance. More atten-
tion should be paid to the onset of cardiac dysfunction in patients with NAFLD/NASH, and the close
communication between hepatologists and cardiologists would be required in the near future.
14 2. Nonalco holic fatty liver disease and cardiovascular disease
I. Liver and heart
https://t.me/medicina_free
Conclusion
There is no doubt that NAFLD/NASH is associated with an increased risk of CVD. It has been suggested that
NAFLD/NASH may contribute not only for the development of atherosclerosis but also the development of cardiac
dysfunction. The number of patients with heart failure is increasing worldwide
[36]. Currently, many clinical guide-
lines for hepatologists have provided the evidence-based guidance for an increased risk of CVD in NAFLD/NASH.
In contrast, some of clinical guidelines for cardiologists have not described the evidence for an increased risk of
CVD in NAFLD/NASH. It is required to accumulate more epidemiological data and to develop clinical guidelines
to remind the cardio-hepatic relationship for general physicians, hepatologists, and cardiologists.
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[16] Anitschkow N. Ueber die veranderungen der kaninchenaorta bei experimenteller cholesterinsteatose. Beitr Pathol Anat 1913;56:379404.
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[18] Dawber TR, Moore FE, Mann GV. Coronary heart disease in the Framingham study. Am J Public Health Nations Health 1957;47:424.
[19] Iso H, Naito Y, Sato S, Kitamura A, Okamura T, Sankai T, et al. Serum triglycerides and risk of coronary heart disease among Japanese
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[20] Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic
fatty liver disease. Ann Intern Med 2005;143:7228.
[21] Kitamura A, Iso H, Naito Y, Iida M, Konishi M, Folsom AR, et al. High-density lipoprotein cholesterol and premature coronary heart dis-
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[22] Imajo K, Hyogo H, Yoneda M, Honda Y, Kessoku T, Tomeno W, et al. LDL-migration index (LDL-MI), an indicator of small dense low-
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[24] Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery dis-
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[26] Koseki M, Hirano K, Masuda D, Ikegami C, Tanaka M, Ota A, et al. Increased lipid rafts and accelerated lipopolysaccharide-induced
tumor necrosis factor-alpha secretion in Abca1-deficient macrophages. J Lipid Res 2007;48:299306.
[27] Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, et al. A lipidomic analysis of nonalcoholic fatty liver disease.
Hepatology 2007;46:108190.
[28] Simonen M, Ma
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nnisto
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V, Leppa
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nen J, Kaminska D, Ka
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V, Venesmaa S, et al. Desmosterol in human nonalcoholic steatohepatitis.
Hepatology 2013;58:97682.
[29] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonal-
coholic fatty liver disease. Nat Genet 2008;40:14615.
[30] Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. WTCCC and the cardiogenics consortium. genomewide
association analysis of coronary artery disease. N Engl J Med 2007;357:44353.
[31] Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of
95 loci for blood lipids. Nature 2010;466:70713.
[32] Hsieh J, Koseki M, Molusky MM, Yakushiji E, Ichi I, Westerterp M, et al. TTC39B deficiency stabilizes LXR reducing both atherosclerosis
and steatohepatitis. Nature 2016;535:3037.
[33] Ekstedt M, Hagstro
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m H, Nasr P, Fredrikson M, Sta
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l P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mor-
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[34] Lee YH, Kim KJ, Yoo M, Kim G, Yoon HJ, Jo K, et al. Association of non-alcoholic steatohepatitis with subclinical myocardial dysfunction
in non-cirrhotic patients. J Hepatol 2018;68:76472.
[35] Canada JM, Abbate A, Collen R, Billingsley H, Buckley LF, Carbone S, et al. Relation of hepatic fibrosis in nonalcoholic fatty liver disease
to left ventricular diastolic function and exercise tolerance. Am J Cardiol 2019;123:46673.
[36] Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: a
report from the American Heart Association. Circulation 2018;137:e67e492.
16 2. Nonalco holic fatty liver disease and cardiovascular disease
I. Liver and heart
https://t.me/medicina_free
CHAPTER
3
Pathophysiologic changes in chronic heart
failure affecting drug pharmacokinetics
Roger K. Verbeeck and Bonifasius S. Singu
School of Pharmacy, Faculty of Health Sciences and Veterinary Medicine, Uni versity of Namibia, Windhoek, Namibia
Introduction
Chronic heart failure (CHF) is a major public health problem with frequent hospitalizations, impaired quality
of life, and shortened life expectancy. In the western countries, 2% of the population is affected by heart failure
and this prevalence increases from 1% at 40 years to 10% among the population over 70 years
[13]. According
to the American Heart Association/American College of Cardiology, CHF is defined as “a complex clinical syn-
drome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to
fill or eject blood”
[2]. Generally, heart failure is a chronic condition but it may also present acutely that is acute
heart failure. Heart failure is traditionally considered to be the result from impairment of the ability of the heart
to pump sufficient amounts of blood into the circulation during systole that is left ventricular systolic dysfunc-
tion. However, heart failure being a common disease in the elderly age, should not be viewed in isolation: ane-
mia, cachexia, chronic pulmonary disease, obstructive sleep apnea, renal dysfunction, hepatic dysfunction, and
diabetes mellitus are conditions frequently observed in patients with CHF and unfavorably affect prognosis.
CHF is a multisystem disorder that affects not only the heart and circulation but also the liver, kidneys, the
gastrointestinal, musculoskeletal, neuroendocrine, metabolic, and immune systems. Heart performance and kid-
ney function are closely interconnected physiologically and pathophysiologically. Ren al dysfunction is highly
prevalent in CHF patients and is an important risk factor for prolonged hospitalization, rehospitalization, and
short- and long-term mortality
[4]. The cardio-renal syndrome is a wide ly accepted concept that describes the
organ-to-organ crosstalk between the diseased heart and the kidney and vice versa
[5]. Accumulating evidence
indicates that organ crosstalk and interaction also occur between the heart and the liver comparable to what is
known for cardio-renal syndrome
[68]. Cardio-hepatic syndrome includes a variety of acute and chronic condi-
tions, where the primary failing organ can be either the heart or the liver. The fundamental mechanisms underly-
ing cardiac hepatopathy are arterial hypoperfusion, which predominates in acute heart failure and leads to
hypoxic hepatitis, and increased right atrial and inferior venous caval pressures in CHF leading to hepatic con-
gestion
[8,9]. On the other hand, cirrhosis is associated with significant cardiovascular abnormalities. The term
“cirrhotic cardiomyopathy” describes impaired contractile responsiveness to stress, diastolic dysfunction, and
electrophysiological abnormalities in patients with cirrhosis without known cardiac disease
[10]. CHF also leads
to pathophysiological changes in the gastrointestinal system
[11,12]. Significant morphological and functional
alterations of the intestine in advanced CHF lead to gastrointestinal manifestations including ascites, protein-
losing enteropathy, and cachexia. Intestinal hypoperfusion and gut mucosal edema may lead to altered gut
permeability. Protein-losing enteropathy leads to hypoalbuminemia, which is an independent predictor of poor
prognosis
Table 3.1.
The New York Heart Association (NYHA) classification has traditionally been used to classify severity of heart
failure and indicate prognosis and, thus to guide patient management (
Table 3.1). Pharmacological treatment var-
ies according to the type of heart failure that is acute or chronic with preserved or reduced ejection fraction
[13].
17
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00015-2 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
Patients with acute heart failure generally require hospitalization and urgent treatment with intravenous vasodi-
lators, inotropes, and/or diuretics. For patients with reduced or preserved ejection fraction, pharmacotherapeutic
agents from different drug classes may be used to relieve symptoms, prevent hospital admission, and prolong
survival: angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, mineralocorticoid/aldosterone receptor
antagonists, angiotensin receptor blockers, digoxin, and diuretics
[13,15]. Several other classes of drugs are rou-
tinely prescribed in patients with heart failure, for example, to prevent atherothrombotic events and arrhythmias,
and to treat various comorbidities. Because of the existence of several heart failure subtypes, interpatient variabil-
ity in disease severity, and the impact of heart failure on hepatic and renal function, drug dosage regimens of car-
diac and noncardiac drugs should be individualized according to the disease-induced pathophysiological
changes that may influence the pharmacokinetics of drugs.
Fundamental clinical pharmacokinetic principles
Clearance concepts
In the 1970s, pharmacokineticists realized that clearance, not half-life, is the preferred measure of the body’s
ability to eliminate drugs
[1618]. The introduction of clearance concepts in pharmacokinetics made it possible
to better predict how changes in liver and kidney function would translate into patient drug dosing. These clear-
ance concepts are based on the relationship between three physiologic parameters, that is organ blood flow (Q),
the intrinsic ability of the eliminating organ to remove unbound drug from the blood in the absence of flow or
protein binding limitations (CL
int
), and the unbound fraction of drug in blood (fu
b
). Since their development in
the 1970s, clearance concepts have been widely used to explain the effects of changes in these physiologic para-
meters that are CL
int
,fu
b
, and Q, as a result of disease states, age, or drug-drug interactions, on the systemic
exposure to drugs following different routes of administration.
From a clinical appli cation standpoint, the drug’s blood (plasma) clearance is the most important pharmacoki-
netic parameter. The area under the drug’s blood
(plasma) concentration-time curve (AUC), a measure of systemic exposure to the drug, is determined by the
fraction of the administered dose reaching the systemic circulation in intact form (F), and the drug’s blood
(plasma) clearance (CL):
AUC 5
F 3 dose
CL
ð3:1Þ
The intensity and likelihood of the drug’s effect are related to the systemic exposure of the patient to the drug.
At steady state, the blood (plasma) concentrations of the drug (C
ss
) are determined by the dosage regimen, that is
maintenance dose (D
M
), dosing interval (τ), F, and the drug’s blood (plasma) clearance (CL), as follows:
C
ss
5
F 3 D
M
τ 3 CL
ð3:2Þ
Therefore the dosing rate (i.e., D
M
/τ) in a particular patient to reach the target systemic steady concentration
of the drug is determined by two pharmacokinetic parameters: F and CL. When the drug is administered
TABLE 3.1 New York Heart Association functional classification of heart failure [13,14].
Class Description
NYHA I Mild; no limitation of physical activity.
NYHA II Mild; no symptoms at rest; slight limitation of physical activity: comfortable at rest, but ordinary physical activity results in
undue breathlessness, fatigue, or palpitations.
NYHA III Moderate; no symptoms at rest; marked limitation of physical activity: comfortable at rest, but less than ordinary physical
activity results in breathlessness, fatigue, or palpitations.
NYHA IV Severe; symptoms at rest; unable to carry out any physical activity without discomfort.
Adapted from McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Bo
¨
hm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart
failure 2012. Eur Heart J. 2012; 33(14):17871847; Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Ren Physiol. 2003;
284:F11F21.
18 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics
I. Liver and heart
https://t.me/medicina_free
intravenously, F is by definition complete, that is F 5 1. When the drug is administered orally (the most common
extravascular route of administration), F may be less than 1 due to incomplete absorption from the gastrointesti-
nal tract, first-pass metabolism in the gut wall, and/or the liver. Therefore the correct choice of the maintenance
dose should be based on an estimate of these two parameters for the individual patient. CL is, in general, the
more important parameter of the two because for most drugs the potential interindividual variability in CL is
much larger than that in F
[19].
Hepatic clearance and oral bioavailability
For the majority of drugs (6 75%) metabolism is the major mechanism for drug elimination from the body
[20]. Hepatic elimination of drugs occurs mainly via metabolism, although for some drugs biliary excretion in
unchanged form may be important. Liver blood flow, reversible binding to plasma proteins and red blood cells,
the activity of the drug-metabolizing enzymes, and, consequently, the blood (plasma) clearance of many drugs
depend on the normal functioning of the liver. Hepatic drug clearance (CL
H
), defined as the volume of blood (or
plasma) which is completely cleared of drug by the liver per unit time, is a function of liver blood flow (Q
H
) and
the hepatic extraction ratio of the drug (E
H
):
CL
H
5 Q
H
3 E
H
ð3:3Þ
In terms of the well-stirred (or venous equilibration) model, one of the organ clearance models introduced in
the 1970s, which is still widely used, hepatic drug clearance then becomes
[17,18]:
CL
H
5 Q
H
3
fu
b
3 CL
int
Q
H
1 fu
b
3 CL
int
ð3:4Þ
where CL
int
is the intrinsic hepatic clearance of the drug. Q
H
, hepatic blood flow, is approximately 1500 mL/min
in a 70 kg healthy adult, which corresponds to approximately 800 mL of plasma flowing through the liver per
minute. As whole blood delivers drug to the liver, ideally blood flow should be used in these equations.
However, in pharmacokinetic studies, concentrations of drugs are most commonly measured in plasma, and this
may introduce substantial errors in the estimation of the in vivo extraction ratio
[21]. Similarly, the fraction
unbound (fu) should refer to blood, not plasma. However, the fraction of unbound drug in plasma (fu) and
in blood (fu
b
) can be assumed to be equivalent as long as the ratio of plasma-to-blood does not differ by more than
a factor of two. When the plasma-to-blood ratio is much smaller than one this assumption is no longer valid and
the necessary correction will have to be made
[22,23].
Drugs can be categorized according to the efficiency of the liver to remove them from the systemic circulation
as having a low (E
H
, 0.3), intermediate (0.3 # E
H
# 0.7), or high (E
H
. 0.7) extraction ratio. For low extrac-
tion ratio drugs (fu
B
3 CL
in t
,, Q
H
), CL
H
is mostly determined by fu
b
and CL
int
that is CL
H
D fu
b
3 CL
int
,
and is enzyme/transporter capacity limited. The hepatic clearance of high extraction ratio drugs (E
H
. 0.7 when
fu
b
3 CL
int
.. Q
H
), on the other hand, will be approximated by Q
H
and, therefore is mostly dependent on
hepatic blood flow, that is CL
H
D Q
H
. For drugs with an intermediate hepatic extraction coefficient
(0.3 # E
H
# 0.7), hepatic clearance will be dependent upon all three parameters, that is the unbound fraction of
drug in blood, the intrinsic clearance of the drug by the liver, and liver blood flow
Eq. (3.4).
For a drug that is mostly eliminated by the liver, the blood (plasma) clearance following “intravenous adminis-
tration” is basically hepatic clearance and is primarily affected by hepatic blood flow when E
H
is high, that is by
the product of the fraction unbound in blood (plasma) and the intrinsic ability of the liver to eliminate the drug
when E
H
is low, and by all three parameters when E
H
is intermediate [17,18,24]. Following “oral administration,”
the drug’s bioavailability (F) is determined by the fraction of the administered dose that is absorbed from the gas-
trointestinal tract into the gut wall and is not transported back into the gut lumen by efflux pumps like P-
glycoprotein (F
a
), by the fraction that passes unchanged through the gut wall into the portal circulation (F
G
), and
by the fraction that escapes first-pass elimination by the liver and passes unchanged into the systemic circulation
(F
H
):
F 5 F
a
3 F
G
3 F
H
ð3:5Þ
The well-stirred model of hepatic clearance predicts that the clearance of an orally administered drug, which
is completely absorbed from the gastrointestinal tract (F
a
5 1) and exclusively eliminated by the liver (F
G
5 1),
is equal to fu
b
3 CL
int
regardless of the drug’s hepatic extraction ratio [17,18]. Also, following oral
19Fundamental clinical pharmacokinetic principles
I. Liver and heart
https://t.me/medicina_free
administration of a drug, which is well absorbed from the gastrointestinal tract (F
a
D 1.0) and which is mostly
eliminated by the liver (F
G
D 1), F can be approximated by
F 5 F
H
5 1 2 E
H
5 1 2 CL
H
=Q
H
ð3:6Þ
Table 3.2 summarizes how the blood (plasma) clearance following intravenous or oral administration of a drug
eliminated exclusively by the liver but with different extraction efficiencies, is affected by Q
H
,CL
int
,andfu
b
.For
example, labetalol is almost completely eliminated by the liver and its blood clearance, approximately 1300 mL/min
in a 70 kg healthy adult, should therefore be very similar to its hepatic clearance
[25].BasedonEq. (3.3) and using
an average hepatic blood flow of 1500 mL/min, it can be derived that the hepatic extraction ratio of labetalol is high
(E
H
D 0.86). Although labetalol is well absorbed from the gastrointestinal tract (F
a
D 1.0), the oral bioavailability of
labetalol is low (F D 0.14) because B86% of the oral dose will be extracted and metabolized during its first pass
through the liver before reaching the systemic circulation
[25]. Because labetalol has a high extraction ratio
(E
H
. 0.7) its blood clearance will be mostly dependent on Q
H
following intravenous administration, and on fu
b
and CL
int
following oral administration (see Table 3.2). Consequently, changes in the fraction unbound in blood or
the activity of the enzymes responsible for its elimination have an important impact on the clearance of labetalol fol-
lowing “oral administration.” In contrast, following “intravenous administration” of labetalol its clearance depends
mostly on liver blood flow, and changes in fu
b
and CL
int
will have only a minor impact (see Table 3.2).
Warfarin is also mostly eliminated by the liver, but unlike labetalol, the efficiency of the elimination process is
very low (E
H
, 0.01) [26]. Since warfarin’s hepatic extraction ratio is extremely low, and it is well absorbed from
the gastrointestinal tract (F
a
D 1.0), its oral bioavailability is virtually complete (F
H
D 1.0) because less than 1% of
the oral dose will be extracted and metabolized by the liver before reaching the systemic circulation
[26]. Because
the hepatic extraction ratio of warfarin is very small, its blood (plasma) clearance depends on fu
b
and CL
int
fol-
lowing both intravenous and oral administration (see
Table 3.2). Consequently, only changes in the unbound
fraction in blood (plasma) and/or the activity of the enzymes responsible for elimination will affect the systemic
clearance of drugs like warfarin having a low hepatic extraction ratio.
When the hepatic clearance concepts were developed in the 1970s, it was generally assumed that unbound
drug molecules could permeate membranes sufficiently quickly to achieve a rapid equilibrium resulting in equal
unbound concentrations in the systemic circulation and the intracellular environment of the eliminating organ:
CL
int;H
5 CL
int
ð3:7Þ
where CL
int,H
is the intrinsic hepatic clearance based on the unboun d drug concentration in the hepatocyte, and
CL
int
is the intrinsic hepatic clearance as defined above that is the intrinsic ability of the eliminating organ to
remove unbound drug from the blood in the ab sence of flow or protein binding limitation
[27]. More recently, it
has become clear that active transport plays an important role in the pharmacokinetics of many drugs
[27,28].
When a drug requires (a) transporter(s) for its efficient penetration into or out of the liver, the intrinsic hepatic
clearance CL
int,H
is potentially influenced by two new parameters related to hepatocellular uptake and efflux into
the blood circulation, in addition to the intrinsic clearance:
CL
int;H
5
PS
inf
PS
eff
1 CL
int
3 CL
int
ð3:8Þ
where PS
inf
and PS
eff
represent the intrinsic clearance for hepatocellular influx and efflux into the systemic circu-
lation, respectively
[27]. Expanding the hepatic clearance concept to include transporter-related aspects is
TABLE 3.2 The physiologic variables affecting blood clearance (CL) of drugs eliminated exclusively by the liver but with different
extraction efficiencies: intravenous vs. oral administration.
Extraction ratio E
H
IV administration (CL/F
a
) Oral administration (CL/F
b
)
E
H
, 0.3 Bfu
b
3 CL
int
fu
b
3 CL
int
0.3 # E
H
# 0.7
Q
h
3
fu
b
3 CL
int
Q
H
1 fu
b
3 CL
int
fu
b
3 CL
int
E
H
. 0.7 BQ
H
fu
b
3 CL
int
a
IV administration: F 5 1.
b
oral administration: F 5 1E
H
.
20 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics
I. Liver and heart
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necessary to better understand the pharmacokinetics of drugs whose hepatic elimination by metabolism and/or
biliary excretion is uptake limited, which is for example the case for some statins (
Fig. 3.1) [28,29].
Renal clearance
The number of drugs that are completely or almost complet ely eliminated from the body by renal excretion in
unchanged form is rather limited. For example, of the approximately 300 drugs listed in the pharmacokinetic
data table in Appendix II of the eleventh edition of Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, only 22% are eliminated for at least 50% by renal excretion in unchanged form
[30]. Excretion of
drug (in unchanged form) in the urine is the net result of glomerular filtration, tubular secretion, and tubular
reabsorption. Therefore renal clearance (CL
R
) is:
CL
R
5 1 2 F
R
ðÞ3 CL
filtr
1 CL
secr
ðÞ ð3:9Þ
where F
R
is the fraction of filtered and secrete d drug reabsorbed from the lumen of the tubules, CL
filtr
is the fil-
tration clearance, and CL
secr
is the tubular secretion clearance. The general principles underlying the hepatic
clearance process are also applicable to renal clearance CL
R
:
CL
R
5 Q
R
3
fu
b
3 CL
int
Q
R
1 fu
b
3 CL
int
ð3:10Þ
where Q
R
is renal blood flow, fu
b
is the unbound fraction of drug in blood (plasma), and CL
int
is the renal intrin-
sic clearance. Renal blood flow is approximately 1100 mL/min in a 70 kg healthy adult, which corresponds to
approximately 600 mL of plasma flowing through the kidneys per minute. Glomerular filtration of drugs is a
low-efficiency process and, therefore CL
filtr
depends on the glomerular filtration rate (GFR), which is
90120 mL/min in a healthy 70 kg person, and the unbound fraction of drug in blood (plasma). Drugs subjects
to tubular secretion, an active process involving transporters, may have a low, intermediate, or high renal extrac-
tion ratio. For drugs that have a high affinity for the renal secretory transporters, CL
secr
is mostly dependent on
renal blood flow. In contrast, for drugs that are not efficiently transported across the membranes of the renal
tubules, CL
secr
depends on the intrinsic clearance of the tubular secretion process and the fraction of drug
unbound in the blood perfusing the kidneys [23].
Approximately 120 mL of plasma water-containing ions and low molecular weight molecules are filtered each
minute by the glomeruli. Because 99% of the water is reabsorbed, filtered and secreted drug will be highly con-
centrated, especially in the distal and collecting tubules. If the drug is sufficiently lipophilic it will be reabsorbed
by passive diffusion into the peritubular blood capillaries. For weak acids and weak bases, only the undissociated
molecules are lipophilic enough to follow the gradient and diffuse from the tubular lumen to the peritubular
blood. Urine pH (normal range: 4.58.0), together with the pKa of the drug, determines the degree of ionization
of a drug and can, therefore significantly affect renal excretion
[23].
MRP3
MRP4
OATP1B1
OATP1B3
OATP2B1
MRP2
BSEP
MDR1
BCRP
Phase I
metabolism
Phase II
metabolism
HEPATOCYTE
BLOOD
BILE
FIGURE 3.1 Simplified diagram illustrating the role of some transporters affecting hepatic uptake and biliary excretion of drugs and the
interplay of hepatic transporters with phase I and phase II metabolism in the hepatic elimination of drugs (BCRP, breast cancer resistance pro-
tein; BSEP, bile salt export pump; MDR, multidrug resistance protein; MRP, multidrug resistance-associated protein; OATP, organic anion
transporting polypeptide).
21Fundamental clinical pharmacokinetic principles
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Volume of distribution
A loading dose is administered when it is important to rapidly achieve the desired therapeutic plasma concen-
tration. The volume of distribution (V) of a drug is a clinically relevant pharmacokinetic parameter because load-
ing doses are calculated based on the target concentration of drug in blood (or plasma), and the volume of
distribution of the drug:
D
L
5 C
target
3 V ð3:11Þ
where D
L
is the loading dose, C
target
is the target concentration of drug in blood (or plasma), and V is the appar-
ent volume of distribution.
The distribution of a drug from the blood circulation into body tissues and organs is a reversible process,
which depends on the drug’s physicochemical characteristics such as lipophilicity and molecular size, and on its
reversible binding to plasma proteins and tissue macromolecules. Assuming passive diffusion is the only mecha-
nism involved in the movement of drug molecules between the circulation and body tissues, V can be described
as a function of extracellular volume (V
EC
), intracellular volume (V
T
), the fraction of drug unbound in plasma
(fu), and the fraction of drug unbound in tissues (fu
T
):
V 5 V
EC
1 V
T
3
fu
fu
T
ð3:12Þ
Total body water, approximately 42 L in a healthy 70 kg person, is divided between extracellular and intracellular
spaces. The volume of the extracellular space (V
EC
) consists of the intravascular plasmavolume(3.5L)andtheextra-
vascular interstitial space (10.5 L). The volume of the intracellular space (V
T
), therefore is approximately 28 L [31].
Drugs can bind reversibly to plasma proteins as well as tissue macromolecules. A number of weak acids have
high affinity for albumin, whereas weak bases often have high affinity for α
1
-acid glycoprotein and also bind to
albumin
[32,33]. Certain drugs, for example, atenolol, do not bind to plasma proteins (fu 5 1), while others, for
example, warfarin, show a very high plasma binding of approximately 99% or more (fu # 0.01). Drugs that have
a plasma protein binding of 90% or more are considered to be highly bound. The principal concern with plasma
protein binding is related to its variability between and within patients in various therapeutic settings as changes
in the unbo und fraction of drug in plasma can lead to changes in the drug’s volume of distribution and clear-
ance. In addition, after distribution equilibrium is achieved, the concentration of active, unbound drug in intra-
cellular water, including in the target tissue(s), is the same as that in plasma except when carrier-mediated
transport is involved. Consequently, unbound plasma concentrations of drug are more directly related to the
pharmacologic effect than total plasma concentrations. Some drugs, especially weak bases, bind reversibly to tis-
sue macromolecules such as phospholipids and, thus distribute in a large volume
[23].
During the last few decades, it has been shown that numerous drugs are substrates for uptake or efflux trans-
porters. Hence, drugs can concentrate in or can be effectively kept out of certain tissues
[34]. When active trans-
port plays an important role in the distribution of a drug,
Eq. (3.12) has to be adapted to inclu de permeability
due to active uptake (P
uptake
) and efflux (P
efflux
):
V 5 V
EC
1 V
T
3
fu
fu
T
3
P
uptake
P
efflux
ð3:13Þ
Because drugs may bind reversibly to plasma proteins and tissue macromolecules with different affinities, the
volume of distribution of drugs seldom corresponds to a defined physiologic space such as plasma volume
(3.5 L), extracellular water space (14 L), or total body water (42 L). The volume of distribution of small drug mole-
cules, therefore typically ranges from approximately 10 L to several 1000 L
[23].
Half-life
Whereas clearance and volume of distribution are independent parameters, half-life (t
1/2
) is a dependent
variable:
t
1=2
5
0:693
k
5
0:693 3 V
CL
ð3:14Þ
where k is the fractional elimination rate constant, that is the fraction of the amount of drug in the body elimi-
nated per time unit. The blood (plasma) half-life of a drug is the time for the blood (plasma) concentration, and
22 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics
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also for the amount of drug in the body, to fall by one -half. Whereas clearance is the pharmacokinetic parameter
describing the irreversible elimination of drug from the blood circulation, half-life describes the time course of
the drug’s disappearance from the circulation (and from the body), and as such depends not only on drug clear-
ance but also on the drug’s volume of distribution. Consequently, a change in the drug’s blood (plasma) half-life
should always be interpreted as potentially being the result of a change in clearance and/or volume of distribu-
tion of the drug.
Pathophysiological changes affecting pharmacokinetics in patients with chronic heart failure
Heart failure is a complex clinical syndrome due to a decrease in the heart’s pumping actio n. The reduced car-
diac output leads to a reduced delivery of oxygen- and nutrient-rich blood to the tissues and organs, which is
necessary for the normal functioning of the body. Heart failure, therefore has a negative impact on the gastroin-
testinal tract, the liver, and the kidneys, organs that play a crucial role in drug pharmacokinetics. A decreased
perfusion of the liver and the kidneys, which in turn may alter the expression of metabolizing enzymes and/or
transporters playing an important role in the elimination of drugs from the body, can lead to important changes
in drug pharmacokinetics. The effect of heart failure on the oral absorption, distribution, metabolism, and renal
excretion will be described in the following sections.
Intestinal permeability
Heart failure patients exhibit decreased gastric emptying and intestinal motility, reduced splanchnic blood
flow, and structural changes within the intestinal tissues
[35,36]. However, to what extent these changes affect
the intestinal permeability F
a
[see Eq. (3.5)] and oral bioavailability F of drugs is not well known. Sandek et al.
studied the small intestinal permeability in patients with CHF using orally administered sugar probe molecules
[11]. They found that in CHF intestinal permeability was increased for lactulose and sucralose, which cross the
small intestinal epithelium by passive diffusion mainly through paracellular routes. The passive carrier-mediated
transport of D-xylose, on the other hand, was diminished in patients with CHF. Although most drugs used to
treat heart failure are rather lipophilic and rely on passive transcellular diffusion for oral absorption, intestinal
transport of certain hydrophilic drugs is via paracellular tight junctions. For example, the oral bioavailability of
lisinopril, a rela tively hydrophilic ACE inhibitor, is on average approximately 25% in healthy subjects but shows
high interindividual variability
[37]. In patients with CHF (NYHA classes IIIV), the oral bioavailability of lisino-
pril was decreased to approximately 16%
[34]. This finding is not consistent with the results of Sandek et al.
using lactulose and sucralose as markers for intestinal absorption via the paracellular route
[11]. More studies are
clearly needed to better understand how absorption of drugs from the intestinal tract may be affected by CHF.
Loop diuretics are frequently used in the treatment of CHF and their pharmacokinetic characteristics have
been well documented in this patient population
[36,3840]. The oral bioavailability of bumetanide and torse-
mide is almost complete ( . 80%), while that of furosemide is incomplete and highly variable (10%100%)
[41,42]. Absorption and subsequent urinary delivery of orally administered loop diuretics must occur at a rate
sufficient to exceed the threshold for response, otherwise, a diuretic effect will not be obtained
[43]. Several stud-
ies have shown that patients with decompensated heart failure have delayed and erratic absorption of furose-
mide compared with healthy subjects
[44,45]. For example, Vasko et al. demonstrated that the absorption lag
time and t
max
(the time to reach the maximum plasma concentrat ion, C
max
, following oral administration)
decreased by 57% and 27%, respectively, and C
max
increased by 29% when CHF patients improved and their sta-
tus changed from decompensated to compensated heart failure
[45]. These observed changes, which can lead to
inadequate diuretic response, may be due to delayed gastric emptying, reduced intestinal motility, or gut muco-
sal edema. Bumetanide and torsemide seem to be less susceptible to the pathophysiological changes in the gas-
trointestinal tract in patients with CHF
[42].
Hepatic clearance
The majority of drugs are eliminated by hepatic metabolism. For a limited number of drugs, biliary excretion
may also significantly contribute to the drug’s elimination. Blood (plasma) clearance depends on hepatic blood
flow (Q
H
), the fraction of unbound drug in blood (fu
b
), and the intrinsic ability of the liver to eliminate the drug
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