(Circulation. 1998;98:2702-2708.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Modulation by Dietary Salt of Verapamil Disposition in Humans
From the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn (D.D., M.F.F., S.D., R.B.K., D.M.R.); the Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany (M.F.F., H.K.K., M.E.); and the Abteilung für Klinische Pharmakologie, Eberhard-Karls-Universität, Tübingen, Germany (M.E.). Dr Kroemer is now Chair of the Department of Pharmacology, University of Greifswald, Germany.
Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, 532 Medical Research Building-I, Vanderbilt University School of Medicine, Nashville, TN 37232-6602. E-mail dan.roden{at}mcmail.vanderbilt.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism.
Methods and Results—Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed. Plasma concentrations of both unlabeled enantiomers (ie, from oral therapy) were significantly (P<0.05) lower during the high-salt phase (eg, mean area under the time-concentration curve [0 to 12 hours] for S-verapamil: 7765±2591 ng · min · mL-1 [high salt] versus 12 514±3527 ng · min · mL-1 [low salt], P<0.05). Peak plasma concentrations were significantly lower and the extent of PR interval prolongation significantly blunted with the high-salt diet. In contrast, data with labeled drug (ie, reflecting the intravenous route) were nearly identical for the 2 diets.
Conclusions—These data indicate that a clinically important component of presystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.
Key Words: diet • metabolism • sodium • stereoisomers
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
It is increasingly recognized that cytochrome P450 enzymes (CYPs) are expressed not only in the liver but also in the intestine and that the latter is an important site of drug metabolism.1 2 The major intestinal CYP in humans is CYP3A4.3 4 5 CYP3A4 metabolizes both endogenous substrates6 and xenobiotics, including commonly used medications such as quinidine7 and verapamil.6 8 A number of studies have demonstrated that dietary interventions can alter expression of intestinal CYPs and their activity in both animals and humans.9 10 11 Recently, we have found that increasing dietary salt from 10 to 400 mEq/d reduced quinidine availability, determined after single doses of the drug, from 76±17% to 69±12%.12 Importantly, there was a much greater reduction in the area under the time-concentration curves (AUC) in the first hour after drug administration (from 1.6±0.6 to 0.6±0.4 µg · h · mL-1), and there was no effect on elimination rate. Taken together, the data suggested that dietary salt modulated a prehepatic (most likely intestinal) component of quinidine disposition. However, the studies were conducted by administration of oral and intravenous doses of quinidine on separate days, an approach that may lead to experimental error because of day-to-day variability in drug disposition.
Verapamil undergoes greater presystemic extraction (>90%) than does quinidine, and multiple members of the CYP superfamily (CYP3A4, CYP1A2, CYP2C) contribute to its metabolism.8 13 14 It has been shown that during CYP3A induction by rifampin, prehepatic metabolism (presumably in the gut wall) plays a pivotal role in the first-pass metabolism of verapamil enantiomers.15 The finding of significant gut wall metabolism of verapamil, in turn, raises the possibility that this may also be a salt-sensitive component of verapamil metabolism. In clinical practice, verapamil is given in the racemic form, although its electrophysiological effects (eg, PR-interval prolongation) are attributable mainly to the S-enantiomer.16 In this study, we used a stable-isotope approach to evaluate the effect of dietary salt on the disposition of the S- and R-enantiomers of verapamil. Simultaneous administration of the unlabeled drug orally and deuterium-labeled drug intravenously was used to exclude day-to-day variability in drug disposition and to allow us to estimate the extent to which presystemic verapamil clearance is modulated by dietary salt during chronic oral drug administration.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Human Subjects
Six men and 2 women (23 to 37 years old; mean, 29±7 years) participated. No clinically significant abnormalities were found by history, physical examination, or routine laboratory tests, including complete blood count, biochemistry, and ECG. No subject took long-term medications, and all refrained from caffeine and alcohol for the duration of the study. The protocol was approved by the Vanderbilt Institutional Review Board, and all subjects gave written informed consent before entry into the study.
Protocol
During the entire 21-day study period, each participant received
120 mg racemic, unlabeled verapamil twice per day (Isoptin,
Knoll), and the disposition kinetics of verapamil were
assessed on 3 occasions (Figure 1
). The
subjects were randomized to receive 1 of 2 dietary salt sequences. In 5
subjects, verapamil disposition was first assessed after 7
days of a low-salt (10 mEq/d) diet, then after 7 days of a high-salt
(400 mEq/d) diet, and finally after 7 days of the low-salt diet
(protocol A), with the order reversed in the other 3 subjects (protocol
B). The 2 diets were prepared by the metabolic kitchen of
the Vanderbilt Clinical Research Center to be identical, and
supplementary salt tablets (20 mEq of sodium per tablet) were used to
achieve the high-salt diet. The salt tablets were divided up among the
3 meals.
|
The initial diet was continued for 7 days (to ensure both salt balance and steady-state concentrations of verapamil). On day 7 of the study, the disposition kinetics of verapamil were assessed by serial blood sampling over a 12-hour period, as described further below. After the 12-hour sample was obtained, the diet was switched to the next salt regimen and maintained for a further 7 days. Similarly, after the 12-hour sample on study day 14, the diet was switched back and maintained for a final 7 days.
On days 7, 14, and 21, subjects received 5 mg IV of deuterated racemic verapamil (d7-S/R-verapamil; donated kindly by Knoll AG, Ludwigshafen, Germany) over 5 minutes, along with their usual morning dose of verapamil. On these days, no evening dose of oral verapamil was administered. Blood samples (10 mL) were collected from the contralateral arm at times 0, 5, 10, 20, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose. An ECG was recorded with each blood sample. Urine was collected for the 12-hour study period for ascertainment of sodium balance and to measure concentrations of verapamil and its metabolites. On days 3 and 5 of the second and third phases of the study, blood was sampled before the morning dose of verapamil to measure trough verapamil levels on the 2 diets. All blood samples were centrifuged immediately at 2500g for 20 minutes, and the plasma was stored at -20°C until analysis.
Evaluation of Liver Blood Flow
One possible confounding factor in assessing
verapamil pharmacokinetics is salt-induced changes in liver
blood flow. Therefore, liver blood flow was measured by the indocyanine
green (ICG) method on day 5 of the first and second study periods.
Blood samples were obtained 0, 30, 60, 90, 120, 150, and 180 seconds
and at 4, 5, 6, 7, 8, 10, 15, and 20 minutes after a 10-second
injection of ICG (0.5 mg/kg).17 Each subject's own plasma
was used to construct a standard calibration curve for spectroscopic
analysis, and blood clearance (corrected for hematocrit) was
estimated by standard methods.17 The addition of
verapamil to blank plasma did not interfere with the
analysis.
Analytical Method for Determination of Labeled and Unlabeled
Verapamil Enantiomers
Plasma concentrations of
d0-R-verapamil,
d0-S-verapamil,
d7-R- verapamil, and
d7-S-verapamil were
determined by a combination of chiral high-performance liquid
chromatography (HPLC) and gas
chromatography–mass spectrometry by use of previously
reported validated methods.15 18 Quality control samples
for S-verapamil and
R-verapamil were routinely assayed, with an
intra-assay coefficient of variation of <4% and an interassay
coefficient of variation of <9%. Urine samples were analyzed
for verapamil and its metabolites
(norverapamil, D-620, D-715, D-617, D-717, D-703) by HPLC
as previously described.15
PR Interval Analysis
The ECG analysis was performed by an independent
observer blinded to the subject's study protocol. The PR interval was
identified in each of the 12 leads, the data were entered into a
microcomputer via a digitizing tablet for calculation of the interval,
and the mean of the 12 PR intervals was then calculated. Data are
presented here as the PR interval prolongation as a percentage
(%
PR) of the baseline value after intravenous (5-minute
time point) and oral verapamil (3 hours after oral
administration).
Pharmacokinetic Analysis
Peak verapamil concentrations
(Cmax) and peak concentration times
(tmax) were derived directly from the original
measured values. The elimination rate constant
(Kel) was determined by a linear regression
analysis of the terminal portion of the curve of log serum
concentration versus time. The elimination half-life
(t1/2) of verapamil was calculated
from the equation t1/2=ln
2/Kel. The AUC of intravenously
administered labeled verapamil enantiomers
(AUCIV) was calculated by the trapezoidal rule
with extrapolation to infinity. After oral administration,
AUCPO was calculated by the trapezoidal rule over
a dosing interval of 0 to 12 hours. The volume of distribution at
steady state (VSS) was equal to
(dosexAUMC/AUC2), where AUMC is the area under
the first moment of the plasma concentration-time curve (txC versus
t).19 Systemic (plasma) clearance (CL) of
verapamil enantiomers was obtained by
CL=dose/AUCIV. Apparent oral clearance
(CLo) was calculated by
CLo=dose/AUCPO and
bioavailability (F) of verapamil enantiomers by
F=(AUCPOxdoseIV)/AUCIVxdosePO).
Statistical Analysis
An order effect was first sought, and none was found. Therefore,
the pharmacokinetic analysis is presented in terms of
the mean while on the 2 diets, ie, high-salt diet indicates that all
the individual data from the high-salt phase of the 2 protocols were
pooled together and the mean is presented. The same applies to
the low-salt diet. Pharmacokinetic and pharmacodynamic
parameters among the different parts of the study were
compared by repeated-measures ANOVA with subsequent
Student-Newman-Keuls pairwise tests if the null hypothesis of equal
means could be rejected; P<0.05 was considered
statistically significant. All data are presented as
mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Five subjects were randomized to protocol A, ie, the dietary sequence low-high-low-salt diet, and the remaining 3 to the high-low-high sequence of diets (protocol B). Therefore, the total number of times subjects were on the high- and low-salt diets was 11 and 13, respectively. However, 2 subjects had 12-hour urinary sodium values >40 mEq while on low-salt diets, and because of this noncompliance, their data from these study days were excluded from the final analysis. In fact, these 2 AUC0–12 values for unlabeled (oral) verapamil for both enantiomers were >2 SD lower than values for nonexcluded subjects, ie, the excluded data further support our major conclusion that the disposition of orally administered verapamil is sensitive to dietary salt. The remaining 12-hour urinary sodium excretions showed compliance with the diets (10.0±8.8 mEq [low salt] versus 172±53 mEq [high salt], P<0.05). There was no significant difference in the weight of the subjects on the 2 diets (69±15 kg [low salt] versus 70±14 kg [high salt], P=NS).
Examples of plasma concentration-time curves (Figure 2) show that concentrations of unlabeled
drug were lower with the high-salt diet, regardless of dietary order,
whereas there was no effect on concentrations of the deuterated
enantiomer. Significant differences (for both enantiomers) were
observed in AUCPO, particularly in the first 4
hours after a dose, and in Cmax (Table 1, Figure 3). The urinary recovery of each measured
verapamil metabolite was higher (total, 34±14%) with the
high-salt diet (Table 2) versus 24±10%
on the low-salt diet (P=0.09). The lower plasma
concentrations during the high-salt diet were associated with a
reduction in %PR at 3 hours, from +14.9±4.2% to +5.4±2.8%
(P<0.01). In contrast to the data for unlabeled drug, data
for deuterated S- and R-verapamil
(Figure 4; Table 1) were virtually
identical. In agreement with this finding, there was no significant
difference in %PR 5 minutes after intravenous
verapamil on the 2 diets (+12.8±3.4% [low salt] versus
+12.6±5.8% [high salt]).
|
,
S-Verapamil; 
,
S-[2H]-verapamil.
|
|
, Low-salt diet; 
,
high-salt diet.
|
|
Figure 5 shows the time course of
unlabeled S- and R-verapamil trough
levels from day 0 (start of a given diet) to day 7 (study day) on
switching between diets. The data suggest that the transition between
high- and low-salt diets was incomplete at 3 days and may have been
incomplete even at 7 days. There was no significant difference in the
mean liver blood flow on the 2 diets (1.54±0.74 L/min [low salt]
versus 1.57±0.66 L/min [high salt]).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Evaluation of systemic drug availability and the relative contributions of hepatic and extrahepatic drug metabolism requires reliable assessment of systemic and oral clearance. One study design uses separate oral and intravenous administration of drugs, assuming that no changes occur between study days. However, substantial intraindividual interday variations in drug metabolism have been observed.20 The simultaneous administration of labeled drug by one route and unlabeled by another provides a tool for the evaluation of systemic and oral clearance without the need to stop long-term oral dosing.20 21 In this study, the coadministration of deuterium-labeled verapamil by the intravenous route and unlabeled verapamil orally allowed the fate of the drug by both routes of administration, during long-term therapy, to be distinguished. This approach has the important advantage that it minimizes the problem of intraindividual variability in drug clearance, which is particularly important when the bioavailability of high-clearance drugs such as verapamil is assessed.15 In addition, the use of deuterium-labeled drug avoids the use of a radiolabeled tracer.
Using this approach, we have clearly shown that the increase in
first-pass metabolism of both verapamil
enantiomers with salt loading is unassociated with any change in
disposition of intravenously administered drug. Thus, the
difference between the fate of orally administered and
intravenously administered drug must reflect a difference
in drug disposition at a site to which the drug is preferentially
exposed with administration by the oral compared with the
intravenous route. The only such sites are the intestine
and the portal circulation itself; thus, we infer a preferential effect
of dietary salt on intestinal drug disposition. The ECG data were
consistent with the plasma concentration data: %PR after
intravenous administration was comparable on the 2 diets,
whereas %PR after oral administration was significantly reduced on
the high-salt diet. These results are similar to our earlier findings
showing that dietary salt modulates the presystemic disposition of
single doses of orally (but not intravenously) administered
quinidine.12 In the present study, by using the
stable-label approach, we were able to establish that this dietary salt
effect is preserved during long-term oral therapy.
Potential Mechanisms
We considered that dietary salt might alter liver blood flow to
contribute to changes in drug disposition, but we found no such change.
A simple decrease in the extent of verapamil absorption
with the high-salt diet seems unlikely, given the trend toward
increased urinary recovery of verapamil metabolites,
whereas decreased recovery would be expected with decreased absorption.
Indeed, this trend toward higher urinary metabolite concentrations with
the high-salt diet supports the concept of increased
metabolism at an extrahepatic site as an important
underlying mechanism. As discussed above, the intestinal mucosa is
increasingly recognized as a site of presystemic drug
metabolism. For example, induction of CYP3A by rifampin
increased the extent of cyclosporine metabolism
to a greater extent than predicted from a hepatic effect
alone,2 and a similar effect of rifampin on
verapamil metabolism has been
observed.15 Conversely, Gomez and
colleagues22 reported that inhibition of
cyclosporine metabolism by ketoconazole
occurred to a similar or greater extent in the gut wall than in the
liver, an effect attributed to inhibition of CYP3A. Most recently, Lown
and colleagues11 have shown that ingestion of grapefruit
juice inhibits metabolism of the calcium channel blocker
felodipine, and with serial intestinal biopsies, they were able to
demonstrate reduction of CYP3A expression in the intestinal mucosa.
Intestinal drug metabolism by CYP3A may therefore be a
major component of the salt sensitivity of drug disposition that we
have demonstrated. The drug efflux pump P-glycoprotein is
increasingly recognized to play a role in intestinal drug
disposition,23 24 25 so variability in its expression or
function is another possible contributor to the salt effect.
Dietary salt is known to modulate sympathetic function.26 Thus, one possible mechanism underlying the effect of dietary salt on drug disposition may relate to an alteration in sympathetic activity, consistent with reported links between autonomic and gastrointestinal function.27 28 29 Another possibility is that increases in sodium or chloride concentration in the intestinal lumen serve as an initial signal for altered intestinal expression of genes encoding proteins such as CYP3A4 or P-glycoprotein.
Clinical Implications
These findings reinforce the notion that diet can be a major
contributor to interindividual variability in drug disposition, eg,
among ethnic groups.30 The findings may also be important
in determination of drug bioavailability in conditions associated with
altered salt balance. For example, it is known that, after the
administration of equivalent doses, plasma quinidine concentrations are
generally higher in patients with congestive heart failure than in
control groups.31 32 The present findings support the
idea that altered salt balance may contribute. Further, the common
dietary recommendation to decrease salt intake in conditions such as
hypertension or congestive heart failure may well modulate the response
to the drug therapies used to treat the underlying disease.
Limitations of the Study
Although ICG clearance is widely used to estimate liver blood
flow, the technique may involve significant assumptions,33
including that of instantaneous distribution into the plasma
compartment, changes in plasma protein concentration that may
unpredictably alter intrinsic hepatic clearance of ICG,34
incomplete extraction,35 and the accuracy of the
assay.36 However, ICG administration to estimate hepatic
blood flow has been considered an especially useful approach in
comparative studies.37
A major advantage of the technique of coadministering labeled and unlabeled drug by different routes is minimization of day-to-day intrasubject variability in drug disposition.21 38 This approach thus allowed us to estimate the extent to which presystemic verapamil clearance is modulated by dietary salt by studying a relatively small number of subjects. This consideration has also been recognized to apply for drugs that do not undergo extensive first-pass metabolism.39 In this study, each subject was studied on 3 separate occasions. The data therefore represent the analysis of 22 study days (11 each on low-salt diets and high-salt diets). If the data from only the 6 completely compliant subjects are reanalyzed (18 study days: 10 on low- and 8 on high-salt diets), the outcome is not changed.
Sex and genetic factors have been invoked to explain the widely recognized variability in CYP3A, although no strong data in support of this contention are available. Recently, we have found that intestinal and hepatic extraction of the probe drug midazolam are highly variable (regardless of sex) and not correlated with each other.40 Indeed, the findings reported here raise the possibility that some of the recognized variability in CYP3A function may be attributable to variability in dietary salt.
|
Acknowledgments |
|---|
This study was supported by grants from the US Public Health Service (GM-31304, GM-07569), the Robert Bosch Foundation (Stuttgart, Germany), the Deutsche Forschungsgemeinschaft (Fr 1298/1-1 to Dr Fromm; Bonn, Germany), and a grant from the Bundesministerium für Bildung und Forschung (grant 01 EC 9405). Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift of the Daiichi Corporation. We are grateful to Kris Norris, Frank Schönberger, Brenda Leake, and Holly Waldrop for their assistance.
Received June 17, 1998; revision received August 28, 1998; accepted September 9, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest. 1992;90:1871–1878.
2. Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther. 1992;52:453–457.[Medline] [Order article via Infotrieve]
3. Kolars JC, Schmiedlin-Ren P, Dobbins WO III, Schuetz J, Wrighton SA, Watkins PB. Heterogeneity of cytochrome P450IIIA expression in rat gut epithelia. Gastroenterology. 1992;102:1186–1198.[Medline] [Order article via Infotrieve]
4. Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest. 1987;80:1029–1036.
5. Watkins PB. Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am. 1992;21:511–526.[Medline] [Order article via Infotrieve]
6. Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, ed. Cytochrome P450. New York, NY: Plenum Press; 1995:473–535.
7. Guengerich FP, Müller-Enoch, Blair IA. Oxidation of quinidine by human liver cytochrome P-450. Mol Pharmacol. 1986;30:287–295.[Abstract]
8. Kroemer HK, Gautier JC, Beaune P, Henderson C, Wolf CR, Eichelbaum M. Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:332–337.[Medline] [Order article via Infotrieve]
9. Hakkak R, Ronis MJJ, Badger TM. Effects of enteral nutrition and ethanol on cytochrome P450 distribution in small intestine of male rats. Gastroenterology. 1993;104:1611–1618.[Medline] [Order article via Infotrieve]
10.
Kappas A, Anderson KE, Conney AH, Pantuck EJ, Fishman
J, Bradlow HL. Nutrition-endocrine interactions: induction of
reciprocal changes in the delta 4–5 alpha-reduction of testosterone
and the cytochrome P-450-dependent oxidation of estradiol by dietary
macronutrients in man. Proc Natl Acad Sci U S A. 1983;80:7646–7649.
11. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo WS, Watkins PB. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest. 1997;99:2545–2553.[Medline] [Order article via Infotrieve]
12. Darbar D, Dellorto S, Mörike K, Wilkinson GR, Roden DM. Dietary salt increases first-pass elimination of oral quinidine. Clin Pharmacol Ther. 1997;61:292–300.[Medline] [Order article via Infotrieve]
13.
Kroemer HK, Echizen H, Heidemann H, Eichelbaum M.
Predictability of the in vivo metabolism of
verapamil from in vitro data: contribution of individual
metabolic pathways and stereoselective aspects.
J Pharmacol Exp Ther. 1992;260:1052–1057.
14. Busse D, Cosme J, Beaune P, Kroemer HK, Eichelbaum M. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995;353:116–121.[Medline] [Order article via Infotrieve]
15. Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology. 1996;24:796–801.[Medline] [Order article via Infotrieve]
16. Echizen H, Brecht T, Niedergesass S, Vogelgesang B, Eichelbaum M. The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans. Am Heart J. 1985;109:210–217.[Medline] [Order article via Infotrieve]
17. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci. 1961;21:43–57.
18. Fischer C, Schonberger F, Muck W, Heuck K, Eichelbaum M. Simultaneous assessment of the intravenous and oral disposition of the enantiomers of racemic nimodipine by chiral stationary-phase high-performance liquid chromatography and gas chromatography/mass spectroscopy combined with a stable isotope technique. J Pharm Sci. 1993;82:244–250.[Medline] [Order article via Infotrieve]
19. Rowland M, Tozer T. Clinical Pharmacokinetics: Concepts and Applications. Philadelphia, Pa: Lea & Febiger; 1995.
20. Eichelbaum M, Dengler HJ, Somogyi A, von Unruh GE. Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination: studies of the relative bioavailability of verapamil tablets. Eur J Clin Pharmacol. 1981;19:127–131.[Medline] [Order article via Infotrieve]
21. Wood AJJ, Carr K, Vestal RE, Belcher S, Wilkinson GR, Shand DG. Direct measurement of propranolol bioavailability during accumulation to steady-state. Br J Clin Pharmacol. 1978;6:345–350.[Medline] [Order article via Infotrieve]
22. Gomez DY, Wacher VJ, Tomlanovich SJ, Hebert MF, Benet LZ. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther. 1995;58:15–19.[Medline] [Order article via Infotrieve]
23. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995;13:129–134.[Medline] [Order article via Infotrieve]
24. Kivistö KT, Kroemer HK, Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol. 1995;40:523–530.[Medline] [Order article via Infotrieve]
25. Lown KS, Mayo RR, Leichtman AB, Hsaio H, Turgeon K, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, Watkins PB. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997;62:248–260.[Medline] [Order article via Infotrieve]
26. Fraser J, Nadeau JHJ, Robertson DH, Wood AJJ. Regulation of human leucocyte beta receptors by endogenous catecholamines: relationship of leucocyte beta receptor density to the cardiac sensitivity to isoproterenol. J Clin Invest. 1981;67:1777–1784.
27. Sjövall H. Sympathetic control of jejunal fluid and electrolyte transport: an experimental study in cats and rats. Acta Physiol Scand Suppl. 1984;535:1–63.[Medline] [Order article via Infotrieve]
28. Levens NR. Response of isolated rat jejunum to angiotensin peptides. Am J Physiol. 1986;251:G559–G566.
29.
Brunsson I, Fahrenkrug J, Jodal M, Sjöqvist A,
Lundgren O. Substance P effects on blood flow, fluid transport and
vasoactive intestinal polypeptide release in the feline small
intestine. J Physiol. 1995;483:727–734.
30. Zhou HH, Koshakji RP, Silberstein DJ, Wilkinson GR, Wood AJJ. Racial differences in drug response: altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med. 1989;320:565–570.[Abstract]
31. Kessler KM, Lowenthal DT, Warner H, Gibson T, Briggs W, Reidenberg MM. Quinidine elimination in patients with congestive heart failure or poor renal function. N Engl J Med. 1974;290:706–709.
32. Gillis AM, Mitchell LB, Wyse DG, McDonald M, Duff HJ. Quinidine pharmacodynamics in patients with arrhythmia: effects of left ventricular function. J Am Coll Cardiol. 1995;25:989–994.[Abstract]
33.
Burczynski FJ, Pushka KL, Sitar DS, Greenway CV.
Hepatic plasma flow: accuracy of estimation from bolus injections of
indocyanine green. Am J Physiol. 1987;252:H953–H962.
34. Ott P, Keiding S, Bass L. Intrinsic hepatic clearance of indocyanine green in the pig: dependence on plasma protein concentration. Eur J Clin Invest. 1992;22:347–357.[Medline] [Order article via Infotrieve]
35. Cohn JN, Khatri IM, Groszmann RJ, Kotelanski B. Hepatic blood flow in alcoholic liver disease measured by an indicator dilution technic. Am J Med. 1972;53:704–714.[Medline] [Order article via Infotrieve]
36. Thiessen JJ, Rappaport PL, Eppel JG. Indocyanine green pharmacokinetics in the rabbit. Can J Physiol Pharmacol. 1984;62:1078–1085.[Medline] [Order article via Infotrieve]
37. Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9:297–301.[Medline] [Order article via Infotrieve]
38. Eichelbaum M, Somogyi A. Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing: studies with deuterated verapamil. Eur J Clin Pharmacol. 1984;26:47–53.[Medline] [Order article via Infotrieve]
39. Heck HA, Buttrill SE Jr, Flynn NW, Dyer RL, Anbar M, Cairns T, Dighe S, Cabana BE. Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests. J Pharmacokinet Biopharm. 1979;7:233–248.[Medline] [Order article via Infotrieve]
40. Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, Wilkinson GR. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996;59:491–502.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  K. Kosuge, A. I. Chuang, S. Uematsu, K. P. Tan, K. Ohashi, B. C.B. Ko, and S. Ito Discovery of Osmosensitive Transcriptional Regulation of Human Cytochrome P450 3As by the Tonicity-Responsive Enhancer Binding Protein (Nuclear Factor of Activated T Cells 5) Mol. Pharmacol., October 1, 2007; 72(4): 826 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Bhardwaj, H. Glaeser, L. Becquemont, U. Klotz, S. K. Gupta, and M. F. Fromm Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 645 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pauli-Magnus, O. von Richter, O. Burk, A. Ziegler, T. Mettang, M. Eichelbaum, and M. F. Fromm Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 376 - 382. [Abstract] [Full Text]
|
|
|
|
|
|
M. F. Fromm, D. Darbar, S. Dell'Orto, and D. M. Roden Modulation of Effect of Dietary Salt on Prehepatic First-Pass Metabolism: Effects of beta -Blockade and Intravenous Salt Loading J. Pharmacol. Exp. Ther., July 1, 1999; 290(1): 253 - 258. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||