Download Yang ZH, Madinova A, Kozai T, Joch H, Aebi U, Luscher TF

Black HR, Elliott WJ, Weber MA, Frishman WH, Strom JA, Liebson PR, Hwang CT, Ruff DA,
Montoro R, DeQuattro V, Zhang DY, Schleman MM, Klibaner MI.
One-year study of felodipine or placebo for stage 1 isolated systolic hypertension.
Hypertension 2001;38(5):1118-23.
The aim of this randomized, double-blind, parallel group study was to compare the effects of
felodipine with placebo on blood pressure, ventricular hypertrophy and quality of life in 171 stage 1
isolated systolic hypertensive patients (84 male, 87 female; mean age 66 years) for 1 year. The
patients were randomized to receive either felodipine extended-release 2.5 mg or placebo, if the
sitting systolic blood pressure (SBP) was > 140 mm Hg, the dose of felodipine or placebo was
doubled. Significantly more patients withdrew from the placebo than the felodipine group. After 1
year patients were receiving either felodipine or placebo at 2.5, 5 or 10 mg. Felodipine treatment
was associated with significantly greater reductions from baseline in mean trough SBP at all time
points. Mean reductions in trough sitting SBP at week 52 compared with baseline were 11.7 mm
Hg for felodipine and 2.0 mm Hg for placebo. After 52 weeks treatment mean reductions in trough
diastolic blood pressure were 3.0 and 0.1 mm Hg in felodipine and placebo groups, respectively.
Patients randomized to felodipine consistently demonstrated greater mean reductions in blood
pressure regardless of age, gender or ethnicity. Felodipine treatment demonstrated significant
differences compared to placebo with respect to response rates, 62% vs 34%. 9 patients
experienced a worsening of their hypertension, 6 of these were in the placebo group and 3 were in
the felodipine group. The prevalence of blood pressure control at week 52 was significantly
different, 62% felodipine vs 32% placebo. The mean left ventricular mass index did not change
between the groups after 52 weeks treatment. 13% of the felodipine treated patients had left
ventricular hypertrophy (LVH) after 52 weeks compared with 33% in the placebo group. 7% of
patients that did not have LVH at baseline developed it during the study in the felodipine group
compared with 24% in the placebo group. Felodipine treatment had significantly better scores on
anxiety and depression than placebo did. 7 patients discontinued treatment due to adverse reactions,
2 patients were from the felodipine group and 5 from the placebo group. Dizziness, back pain and
headache were more common in the placebo-treated patients, while hematuria, rhinitis and
dyslipidemia were more common in the felodipine-treated patients. The authors conclude that
felodipine treatment reduced progression to the higher stages of hypertension, reduced the
incidence of LVH and improved an overall measure of the quality of life.
Morgan TO, MacInnis R, Bertram D, Anderson AE.
The effect of candesartan, felodipine or their combination on 24 h blood pressure and
microalbuminuria.
Journal of Hypertension 2001;19(Suppl 2):S174, Abs 7C.5.
In this double-blind crossover study 32 patients received candesartan 16 mg, felodipine 5 mg,
candesartan + felodipine or placebo. Mean 24-h ambulatory blood pressure fell 12.3/6.8 mm Hg in
the candesartan group, 12.0/5.5 mm Hg in the felodipine group and 21.0/10.2 mm Hg in the
candesartan + felodipine. 22 patients taking candesartan + felodipine, 5 patients taking candesartan
and 5 patients taking felodipine achieved their lowest 24-h ambulatory blood pressure. The blood
pressure reduction with combined therapy was additive and consistent over day and night. In the 14
patients with microalbuminuria, urinary albumin excretion rates were 192 mcg/min in the placebo
group, 101 mcg/min in the candesartan group, 181 mcg/min in the felodipine group and 93
mcg/min in the candesartan + felodipine group. Falls in microalbuminuria did not correlate with
falls in blood pressure. All drugs were well tolerated. The authors conclude that blood pressure is
reduced more effectively by candesartan + felodipine than by either drug alone, and that
candesartan reduces microalbuminuria.
Morgan TO, MacInnis R, Bertram D, Anderson AE.
The effect of candesartan, felodipine or their combination on 24h ambulatory blood pressure.
American Journal of Hypertension 2001;14(4 Pt 2):27a, Abs O-57.
In this double-blind crossover study 36 patients (all aged > 65 years) with systolic hypertension
received candesartan 16 mg, felodipine 5 mg, candesartan + felodipine or placebo. 32 patients
completed all treatment periods and underwent 24-h ambulatory blood pressure measurements and
clinic blood pressure measurements at the end of each treatment period. Systolic and diastolic
ambulatory and clinic blood pressure readings for felodipine, candesartan, felodipine + candesartan
and placebo are shown in a table. Blood pressures were lower in the felodipine and candesartan
groups than in the placebo groups. Felodipine + candesartan treatment had an additive effect,
causing a fall in blood pressure greater than that achieved by either drug alone. All treatments were
well tolerated. The authors conclude that candesartan + felodipine is a more effective treatment for
hypertension than either drug alone due to an additive effect of the 2 drugs.
Dopp JM, Ernst ME, Dellsperger KC, Phillips BG.
Comparison of amlodipine and felodipine on 24-hour ambulatory blood pressure in
hypertensive patients.
American Journal of Hypertension 2001;14(4 Pt 2):118a, Abs P-267.
Heart rate and 24-h ambulatory blood pressure values were compared in 50 patients (mean age 56
years) with mild-to-moderate hypertension who were randomized to 8 weeks of amlodipine 5
mg/day (n = 24) or felodipine 5 mg/day (n = 26). Doses of both drugs could be doubled if needed to
obtain blood pressure control. Mean daily doses at the end of the study were amlodipine 8 mg and
felodipine 7 mg. Mean 24-h ambulatory blood pressure values were significantly lower in
felodipine than in amlodipine patients after 1 week of therapy, but both drugs significantly and
similarly decreased mean 24-h ambulatory blood pressure as well as daytime and nighttime
ambulatory blood pressure after 8 weeks of therapy. The authors conclude that felodipine decreased
blood pressure sooner than did amlodipine, but that both agents have similar antihypertensive
effects after 8 weeks of therapy.
Mancia G, Omboni S, Parati G, Clement DL, Haley WE, Rahman SN, Hoogma RPLM.
Twenty-four hour ambulatory blood pressure in the Hypertension Optimal Treatment (HOT)
study.
Journal of Hypertension 2001;19(10):1755-63.
In this Hypertension Optimal Treatment (HOT) sub-study, patients (n = 277, 54% male; mean age
62 years) underwent both office measurements and 24 h ambulatory blood pressure measuring to
determine the extent of which antihypertensive treatment modifies daily life blood pressure. All
patients were randomized to reach a target diastolic blood pressure < = 90 mm Hg, < = 85 mm Hg
or < = 80 mm Hg by administering a 5 step drug treatment. Step 1 consisted of administration of
felodipine 5 mg plus a low dose of ACE inhibitor or beta-blocker. Step 2 involved felodipine 10 mg
plus the previous dose of ACE inhibitor or beta blocker. Step 3 included felodipine 10 mg
administration plus a higher ACE inhibitor or beta-blocker dose. Step 4 equated to step 3 with the
addition of hydrochlorothiazide. Step 5 equated to step 3 plus other hypertensive drugs. When these
steps were completed the patients were randomized to take a daily dose of acetylsalicylic acid 75
mg or placebo in a double-blind fashion. Significantly when patients were taking felodipine only, it
was found that heart rate was not increased. It is evident from the results of this study that, before
treatment, 24 h diastolic and systolic average blood pressures were substantially less than the
corresponding office values; and this is consistent with similar studies.
Yang ZH, Madinova A, Kozai T, Joch H, Aebi U, Luscher TF.
Felodipine inhibits nuclear translocation of p42/44 mitogen-activated protein kinase and
human smooth muscle cell growth.
Cardiovascular Research 2002;53(1):227-31.
The aim of this study was to determine whether felodipine interferes with the p42/44 mitogenactivated protein kinases pathway, and thereby arrest cell growth. As part of the DNA synthesis
study section of the study, smooth muscle cells were stimulated with platelet-derived growth factor
for 24 h in the presence or absence of felodipine. For the activation of p42/44 mitogen-activated
protein kinases and Elk-1 activation part of the study smooth muscle cells were stimulated with
platelet-derived growth factor for 15 rnin in the presence or absence of felodipine and then
harvested in extraction buffer. The results of the study showed that stimulation of human smooth
muscle cells with platelet-derived growth factor for 24 h enhanced thymidine incorporation. This
process was prevented in the presence of felodipine. Activation of p42/44 mitogen-activated
protein kinases was not influenced by felodipine. The results also showed that platelet-derived
growth factor induced translocation of p42/44 mitogen-activated protein kinases from the
cytoplasm to the cell nucleus, this was inhibited by felodipine. Furthermore, 1 of the nuclear
protein substrates of p42/44 mitogen-activated protein kinases, Elk-1, was phosphorylated by
platelet-derived growth factor, a process which was inhibited by felodipine. This further confirmed
that the entry of p42/44 mitogen-activated protein kinases into the nucleus was prevented by
felodipine.
Zabalgoitia M, Rahman SNU, Haley WE, Yarows S, Krause L, Anderson LC, Oraby MA,
Amarena J.
Effect of regression of left ventricular hypertrophy from systemic hypertension on systolic
function assessed by midwall shortening (HOT echocardiographic study).
American Journal of Cardiology 2001;88(5):521-5.
A study was carried out in order to determine whether regression of left ventricular (LV)
hypertrophy is associated with an improvement in the ventricular mechanics in patients with
pressure-overload hypertrophy. A number of patients from the HOT trial (n=508, 58% male; mean
age 60 years) were entered into this study and underwent serial echocardiographic examinations.
These patients were given felodipine, followed by the addition of either an ACE inhibitor or a betaadrenergic blocking agent, and hydrochlorothiazide until the target diastolic blood pressure was
reached. Echocardiograms were carried out at baseline during the 2-week washout phase before
starting therapy with felodipine at year 1, year 2, and at the end of the study. Over the course of the
study, there was a large reduction in both systolic and diastolic blood pressure. The authors
conclude that midwall shortening is a more sensitive index of systolic function in patients with
pressure-overload hypertrophy, and it identifies high-risk patients who may benefit from a more
aggressive antihypertensive program.
Ruzicka M, Leenen FHH.
Monotherapy versus combination therapy as first line treatment of uncomplicated arterial
hypertension.
Drugs 2001;61(7):943-54.
This review discusses the treatment options available for uncomplicated arterial hypertension and
compares monotherapy with combination therapy for control of this condition. The current
recommendation for the treatment of uncomplicated hypertension is mono-drug therapy involving
stepwise dose increases and the addition of a second agent if high doses of the original drug fail to
normalise blood pressure. Combination drug therapy has only recently come under focus. Single
drug regimens address only 1 pathophysiological mechanism of hypertension and the reasons for
the lower response rate to single drug therapy may be because the role of the particular
pathophysiological mechanism may vary from patient to patient. Previous studies involving single
drug therapy with either a diuretic, beta-blocker (atenolol), calcium antagonist or ACE inhibitor
showed that response rates were only around 55%. Another possible contributor to the low
response achieved by single drug therapy for hypertension may be poor adherence to the single
drug regimen, and possible factors which affect patient compliance include cognitive, social and
behavioural elements as well as adverse effects and the complexity of the regimen. Combination
therapy has several advantages over monotherapy especially in terms of antihypertensive
effectiveness at lower doses and thus has a lower incidence of adverse effects. A beta-blocker and
calcium antagonist may complement each other in terms of decreasing peripheral vascular
resistance and cardiac output and in terms of tolerability. The results of several studies have shown
a calcium antagonist/beta-blocker combination to have superior antihypertensive efficacy compared
to each agent alone. One such study involved randomization of patients (n=159) with mild
hypertension to treatment with felodipine 10 mg/day, metoprolol 100 mg/day or a combination of
both for 12 weeks. The response rate, defined as diastolic blood pressure (DBP) lt90mm Hg, was
higher with the combination therapy (71%) than with either agent alone (49% for felodipine, 34%
for metoprolol). A similar study using both these agents for the treatment of patients with mild to
moderate hypertension (n=58) but at lower doses of metoprolol 50 mg/day, felodipine 5 mg/day, or
in combination also showed similar results. After 6 weeks of treatment dose titration was
performed involving an increase in felodipine from 5 to 10 mg/day and metoprolol from 50 to 100
mg/day. 65% of patients had a positive response to the low dose combination which was
significantly higher than either agent alone at the lower or standard dose. Another study
investigated 12 weeks of treatment with a combination of felodipine 5 mg/day combined with
metoprolol 50 mg/day to treatment with the ACE inhibitor enalapril 10 mg/day and placebo. Dose
adjustment was required in 38% of patients receiving the combination because their DPB remained
above 90mm Hg compared to 61% of those receiving enalapril and overall response rates were
highest in the group that received the combination, being 72%, compared to 49% for enalapril and
30% for placebo. In addition the overall incidence of peripheral oedema with calcium antagonists
was also lower when the calcium antagonist was combined with a beta-blocker. The overall
conclusion is that fixed low-dose combination therapies offer superior initial antihypertensive
efficacy and improved tolerability but whether this will lead to better control of arterial
hypertension and thus a further reduction in cardiovascular/cerebrovascular morbidity and mortality
remains to be seen.
Miczke A, Cymerys M, Bryl W, Luczak M, Pupek Musialik D.
The influence of hypertensive drugs on circadian rhythm of blood pressure.
Journal of Hypertension 2001;19(Suppl 2):S81, Abs P1.228.
In this study 39 patients (aged 20-55 years) with mild-to-moderate essential hypertension received
trandolapril, felodipine ER or rilmenidine once daily in the morning for 1 month and in the evening
for 1 month. Office blood pressure and ambulatory blood pressure readings showed significant
reductions of blood pressure in each treatment group. 24-h mean, daytime and nighttime
ambulatory blood pressure readings within each treatment group did not differ between morning
treatment and evening treatment periods. The authors conclude that the effect of time of drug
administration on blood pressure variability is less pronounced than the effect of antihypertensive
treatment itself.
Ahmad S, Keeley PA, Stout MJ, Davidson RC.
Pretreatment hemodynamics predict response to therapy in essential hypertension: HOT substudy.
American Journal of Hypertension 2001;14(4 Pt 2):182a, Abs P-451.
The effects of baseline hemodynamics on response to antihypertensive therapy were examined in
this sub-study of the Hypertensive Optimum Therapy (HOT) clinical trial involving 10 patients
with hypertension well-controlled by felodipine monotherapy and 51 patients randomized to the
addition of enalapril or metoprolol to the felodipine. Patients with poor responses to the addition of
enalapril or metoprolol after 3 months were crossed over to the other therapy. Baseline cardiac
indices were significantly higher and total peripheral resistance was significantly lower among
patients who required metoprolol for blood pressure control (n = 16) compared with those whose
blood pressure was controlled by felodipine alone or with enalapril initially or after crossover (n =
45). The authors conclude that baseline hemodynamics appear to predict responsiveness to
antihypertensive therapy.
Coca A, Calvo C, Sobrino J, Olivan J, Garcia Puig J, Otero A, Alberti F, Martin Hidalgo A, Ocon J.
Low-dose fixed combination therapy is superior to dose increase in patients not controlled by
monotherapy.
American Journal of Hypertension 2001;14(4 Pt 2):175a, Abs P-428.
This multicenter study examined 24-h ambulatory blood pressure levels in 154 patients (53% male,
47% female; mean age 54 years) with uncontrolled essential hypertension who were randomized
double-blind to 12 weeks of once-daily treatment with a fixed-dose of felodipine 5 mg/ramipril 5
mg or to monotherapy with once-daily felodipine 10 mg or ramipril 10 mg. These patients had
previously failed therapy with 4 weeks of once-daily felodipine 5 mg or ramipril 5 mg and with
ACE inhibitors and calcium channel blockers, respectively. 24-h systolic and diastolic pressures
were decreased significantly more by the combination therapy and by felodipine 10 mg than by
ramipril 10 mg. Office blood pressure control was significantly greater with combination therapy
than with either monotherapy. Fewer side effects occurred in patients treated with the combination
therapy than in those treated with felodipine 10 mg (28% vs 41%). The authors conclude that lowdose fixed combination therapy is a better treatment option than dose increase for patients with
uncontrolled hypertension.
Coca A, Calvo C, Sobrino J, Olivan J, Garcia Puig J, Otero A, Alberti F, Martin Hidalgo A, Ocon J.
Combination therapy is a better strategy than increasing the dose in hypertensive patients not
controlled by monotherapy. A double-blind randomized study.
Hypertension 2001;37(3):996.
In this multicenter, double-blind study 210 patients with essential hypertension received either
felodipine 5 mg/day or ramipril 5 mg/day for 4 weeks followed by placebo for 2 weeks. 154
patients (mean age 54 years) were eventually randomized to receive felodipine 5 mg/day + ramipril
5 mg/day, felodipine 10 mg/day or ramipril 10 mg/day for 12 weeks. 24-h ambulatory monitoring
was performed before randomization and at 12 weeks. Systolic blood pressure was reduced by 16.5
mm Hg in the felodipine + ramipril group, 16.7 mm Hg in the felodipine group and 9.3 mm Hg in
the ramipril group. Diastolic blood pressure was reduced by 11.4 mm Hg in the felodipine +
ramipril group, 11.9 mm Hg in the felodipine group and 7.2 mm Hg in the ramipril group. Blood
pressure control was achieved by 46% of patients taking felodipine + ramipril, 28% of patients
taking felodipine and 25% of patients taking ramipril. 28% of patients taking felodipine + ramipril
and 41% of patients taking felodipine experienced adverse events. The authors conclude that lowdose fixed-combination therapy is better than increased dosage for essential hypertension not
controlled by monotherapy.
Zebekakis PE, Tziolas J, Lasaridis AN, Tourkantonis AA.
Treatment of isolated systolic hypertension in a comparative study of four antihypertensive
drugs.
American Journal of Hypertension 2001;14(4 Pt 2):99a, Abs P-209.
Blood pressure was monitored in 106 patients (mean age 62.9 years) with isolated systolic
hypertension who were randomized to once-daily treatment with amiloride 2.5-5 mg/chlorthalidone
25-50 mg, atenolol 50-100 mg, perindopril 2-4 mg or felodipine 5-10 mg in this parallel group
study. If target blood pressure (systolic pressure < 140 mm Hg) was not met after 4 weeks of
monotherapy, dual therapy and then triple with a combination of the study drugs were instituted,
each for an additional 4 weeks. 96 patients completed the study. 2 patients withdrew due to cough
and 8 due to peripheral edema. All of the treatments significantly reduced blood pressure. The
target blood pressure was achieved by 88% of the patients receiving felodipine, 65% of the patients
receiving atenolol, 75% of the patients receiving amiloride/chlorthalidone and 62% of the patients
receiving perindopril. Dual and triple therapy was required by 27% and 9.3% of the patients,
respectively. The authors conclude that the drugs studied were effective as mono- and combination
therapy, with a rank order of felodipine, amiloride/chlorthalidone, atenolol and perindopril.
Schleman MM, Hwang C, Plendil HF Study Group.
Acute and chronic hemodynamic effects of felodipine ER in patients with chronic heart
failure (NYHA Class II-IV).
Journal of Cardiac Failure 2001;7(3)(Suppl 2):66, Abs 243.
In this study 151 patients (aged 27-78 years) with heart failure received Plendil (felodipine ER)
1.25 mg, 2.5 mg, 5 mg or 10 mg or placebo single dose and twice daily for 12 weeks. Cardiac index
and stroke volume index increased significantly after both acute and chronic felodipine dosing
compared with placebo. Systemic vascular resistance decreased after acute dosing. Pulmonary
artery pressure and pulmonary capillary wedge pressure were not affected by felodipine. Heart rate
and mean blood pressure were affected only by felodipine 10 mg. No significant improvements in
heart failure symptoms and no changes in assessment of global response by physicians or patients
were seen after felodipine treatment. 12% of patients taking placebo, 19% of patients taking
felodipine 1.25 mg, 20% of patients taking felodipine 2.5 mg, 16% of patients taking felodipine 5
mg and 37% of patients taking felodipine 10 mg discontinued the study due to adverse events.
More weight gain, edema and orthopnea were seen in the felodipine 10 mg group. The authors
conclude that felodipine ER produces acute hemodynamic changes that are sustained for 12 weeks
and is well tolerated up to 5 mg twice daily.
Morgan TO, Anderson AIE, MacInnis RJ.
ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic
hypertension
American Journal of Hypertension 2001;14(3):241-7.
The intent of this balanced randomized crossover study of 74 elderly patients with untreated
hypertension (56 male, 18 female; aged 77.3 years mean) was to determine which drug class
lowered blood pressure most effectively, the percentage of patients controlled with single or
sequential monotherapy, and if response to 1 drug class determined response to other drug classes.
The ACE inhibitors used included enalapril 20-40 mg (n=24) and perindopril 4-8 mg (n=38).
Calcium channel-blocking drugs included felodipine (n=26) and amlodipine 5-10 mg (n=39).
Atenolol 25-50 mg was the beta-blocker included. The diuretic used was hydrochlorothiazide 25-50
mg. Patients received the low dose for 1 month and the high dose for 1 month. Only calcium
channel blockers showed a dose-dependent increase in response. Systolic blood pressure (SBP) was
lower than placebo with all drug classes, but this difference was not significant for the beta-blocker.
Pulse rate decreased with beta-blocker use. The decrease in SBP was ACE inhibitors = beta-blocker
< diuretics = calcium channel-blocking drugs. The decrease in diastolic blood pressure (DBP) was
< the decrease in SBP and no significant differences were noted in the DBP among the drug
classes. A total of 21-35% and 16-18% of the patients were universal responders and
nonresponders, respectively, to the drugs used. The patient's well being was lower with betablockers. Adverse effects included headache, faintness, lethargy, flushing, cough, wheeze,
breathlessness, sexual dysfunction, itch, cramps, ankle swelling, nausea, sleep disturbances, skin
rash, and hypertension. Only beta-blockers had more side effects than placebo. The authors
conclude that elderly patients with essential hypertension are recommended to start a low dose
calcium-channel blocker or diuretic regimen.
Butani L, Berg G, Makker SP.
Effect of felodipine on tacrolimus pharmacokinetics in a renal transplant recipient.
Transplantation 2002;73(1):159-60.
This letter reports the case of 13-year-old boy for whom pharmacokinetic interactions occurred
between felodipine and tacrolimus. The patient underwent a renal transplantation. He was treated
with prednisolone 50 mg/day, tacrolimus 4 mg bid, mycophenolate mofetil 500 mg bid, oral
ganciclovir 1 g tid, trimethoprim-cotrimoxazole 80 mg/day and fluconazole 100 mg/day. On
postoperative day 15, felodipine (2.5 mg/day) was initiated to treat hypertension. In the following
weeks tacrolimus levels became very high necessitating several dose reductions. After fluconazole
discontinuation, tacrolimus dose was increased again to maintain target trough levels.
Normalization of blood pressure was observed 8 months after transplantation inducing a
discontinuation of felodipine. A week later levels of tacrolimus dropped and the dose had to be
increased. According to the authors, the changes in the levels of tacrolimus were the results of a
significant interaction between felodipine and tacrolimus. The authors report a study conducted by
Cohen with felodipine and cyclosporine which showed no effect of the coadministration of the 2
drugs on cyclosporine trough levels.
Dresser GK, Wacher V, Ramtoola Z, Cumming K, Bailey D.
Peppermint oil increases the oral bioavailability of felodipine and simvastatin.
Clinical Pharmacology & Therapeutics 2002;71(2):P67.
The pharmacokinetics of felodipine and simvastatin, when administered in combination with
peppermint oil, grapefruit juice or water, were compared in 2 3-way crossover studies involving 12
healthy volunteers. Subjects received felodipine 10 mg extended release tablet or simvastatin, with
either water, peppermint oil capsules or grapefruit juice. AUC's for felodipine were found to be 23,
30 and 37 with water, peppermint oil and grapefruit juice, respectively. Cmax's for felodipine were
5, 7 and 9 with water, peppermint oil and grapefruit juice, respectively. The authors suggest that a
lower interaction with felodipine than with simvastatin was expected, based on the idea that the oral
bioavailabilities of felodipine (15%) and simvastatin (2%) were correlated with cytochrome
CYP3A4 activity. The AUC's of both felodipine and simvastatin were increased by 30% with the
addition of peppermint oil. The addition of grapefruit juice increased the AUC's of felodipine and
simvastatin by 60% and 300%, respectively. It is suggested that both CYP3A4 and "P-gp" efflux
transport are limited by grapefruit juice. It is thought that simvastatin, but not felodipine, is a "Pgp" substrate. The authors conclude that peppermint oil selectively blocks CYP3A4 activity and
may be used to increase oral bioavailability of a drug if CYP3A4 activity reduces systemic
availability.