BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 8, 285-297 (1987)

PHYSIOLOGICAL PHARMACOKINETICS AND

FEMALE RATS PHARMACODYNAMICS OF (I-)-VERAPAMIL IN

ELIZABETH L. TODD AND DARRELL R. ABERNETHY

Department of Medicine, Section on HypertensionlCIinical Pharmacoiogy, Baylor College of Medicine, Houston, Texas.

ABSTRACT

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1 , 3 , 5 , 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats recieving i.p. (mean k S.D.) (2.28 k 0.72 per cent) and i.v. (2.08 k 0.03 per cent) verapamil. MAP and verapamil concentration in plasma ( r = 0.75; p < 0.01) and cardiac muscle ( r = -0.82; p < 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapa- mil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.

KEY WORDS Verapamil Tissue distribution Rats Pharmacokinetics Pharmacodynamics

Addressee for correspondence and Current Address: Darrell R. Abernethy, M.D. , Ph.D. , Director, Division of Clinical Pharmacology, Brown University, Department of Medicine, Roger Williams General Hospital, 825 Chalkstone Avenue, Providence, Rhode Island 02908, U S . A .

0142-27821871030285-13$06.50 Received 9 May I986 @ 1987 by John Wiley & Sons, Ltd. Revised 10 October 1986

286 E. L. TODD AND D. R . ABERNETHY

INTRODUCTION

Verapamil, a widely used calcium channel antagonist, exhibits both a negative dromotropic effect on atrioventricular (AV) conduction' and a direct vasodilatory effect .2 There is good correlation between P-R prolongation (used as a measure of AV nodal conduction delay) and verapamil plasma concentration in humans3 and dogs4 after i.v. administra- tion. However, after oral administration, correlation between concentration and effect are more variable and plasma concentrations two or three times those attained after i.v. administration are necessary to produce similar AV nodal conduction delay.3 It has also been shown in human studies that pharmacokinetics of verapamil are changed in obesity due to an increased volume of distribution5 and in the elderly due to decreased total clearance.6 The time course of tissue distribution and detailed compartmental distribution of verapamil between i.p. (here used as a model of human oral dosing) and i.v. dosing in an animal model may provide insight into differences in drug effect which are observed after different routes of administration. In addition, studies of drug distribution may establish physiologic compartments of drug distribution which may relate to variability in extent of distribution occurring in vivo in models such as human obesity. Prior studies in which a limited number of tissue compartments were examined suggest that in the dog and rat verapamil distributes extensively into the lung and to a lesser extent into cardiac and skeletal muscle.738

Therefore, the present study was initiated to evaluate the rat as a model for studying both pharmacokinetics and pharmacodynamics of verapamil after i.v. and i.p. administration and to evaluate tissue distribution as a possible source of variation among pharmacokinetics and pharmacodynamic para- meters.

MATERIALS AND METHODS

Chemicals of analytical reagent grade were utilized. Verapamil, norverapa- mil, and D-517 (assay internal standard) were kindly provided by Knoll Pharmaceuticals, Whippany, New Jersey.

Animal studies Female Sprague-Dawley rats weighing 200 to 250 g (Harlan Industries,

Indianapolis, Indiana) were maintained in a temperature-controlled environ- ment with a 12h daily light cycle and with access to tap water and food (Purina Rat Chow) ad lib for a minimum of 3 days. One day prior to drug treatment, rats were anaesthetized with ether and cannulated via the left carotid artery for i.p. dosing studies (n = 30 animals) and additionally via the left jugular vein for i.v. infusion studies (n = 7 animals). For both venous and arterial cannulations, the vessel on the left side of the neck was exposed,

KINETICS AND DYNAMICS OF VERAPAMIL 287

clamped, and cannulated with saline-filled polyethylene cannula (PE-50, Intramedic). The catheter was flushed with saline to insure patency, heat sealed, and tunnelled under the skin to emerge at the back of the neck. Animals were allowed to recover overnight with free access to food and water. After obtaining baseline blood pressure measurement via the carotid line, the conscious animals received either 10mg kg-' verapamil i.p. or an i.v. infusion of 21.7 pg min-' for 20 min followed by an infusion of 3.25 pg min-' for the duration of the experiment. After i.p. injection, blood pressure measurement and plasma (P) samples (200~1) were obtained at 1, 3, 5 , 19, and 24 h. Six of the 30 animals were sacrificed at each of the above times. After light etherization, animals were exsanguinated via the carotid cannula into heparinized tubes for recovery of plasma, and after decapitation, samples of the following tissues-lung (LU), liver (LI), renal medulla (RM), renal cortex (RC), left ventricular cardiac muscle (CM), skeletal muscle (SM), perirenal fat (PF), brain stem (BS), cerebral cortex (CX), and cerebellum (CB)-were removed, rinsed, blotted, homogenized in nine volumes of isotonic phosphate buffer, pH 7.4, and frozen for subsequent analysis of verapamil and norverapamil. MAP was calculated as [(systolic pressure - diastolic pressure)l3] + diastolic pressure.

Animals which received i.v. infusion (n = 7) had reached steady state by 1 h and were sacrificed at 3 or 5 h after the beginning of the infusion. Serial blood pressure determination and plasma sampling were made over the course of the infusion. Animals were sacrificed and tissues obtained as described above.

Protein binding in plasma Binding of verapamil to plasma protein was determined in duplicate for

each animal by dialysing 0.4 ml plasma placed in Spectrapor dialysis tubing (molecular weight cutoff, 12000-14000) against 8 ml isotonic, 0.1 M phosphate buffer, pH 7.4, at 37" for 5 h. Preliminary studies had determined equilibrium to be established by 4 h. Binding was shown to be concentration- independent from 50 to 1500ng ml-' verapamil with complete recovery (97-7 f 4.4 per cent) at all concentrations. Plasma obtained from animals sacrificed at 1, 3 or 5 h after i.p. administration or at the termination of i.v. infusion was used without spiking with additional verapamil for dialysis. Plasma ( lml) from animals sacrificed at 19 and 24h was spiked with verapamil to a concentration of 150 ng ml-' prior to dialysis. Dialysed plasma and dialysate were frozen for subsequent analysis.

Verapamil analysis by GCINPD Samples of plasma (10-100 pl), tissue homogenate, dialysate, and dialysed

plasma were analysed for verapamil and norverapamil by GCMPD.9 Samples were alkalinized with 1ml 1.5 N NaOH and extracted with 8ml hexane:isoamyl alcohol (98:2). The organic phase was then extracted with

288 E. L. TODD AND D . R . ABERNETHY

1.0ml of 0.1 N HC!. The acid phase was alkalinized with 0-5 ml 1.5 N NaOH. Verapamil, norverapamil, and internal standard (D-517) were extracted into 50 pl toluene. The toluene extract (1-4 pl) was used for chromatographic separation with a 0.91 meter 3 per cent SP2250 (Supelco) column at 290". Sensitivity of the assay in the tissue and rat plasma matrix was greater than that noted in human plasma, with verapamil concentrations of 0.2 ng ml-' or gram of tissue detected.

Pharmacokinetic analysis and calculations All data are presented as mean f standard deviation (S.D.). Terminal

elimination half-life (t,h beta) of verapamil in plasma and tissue after i.p. verapamil doses was calculated by least squares regression analysis of the mean of each set of data points from time points, 1 ,3 ,5 , and 19 h (Figure 1). After i.v. verapamil infusions, steady state clearance was determined by the relationship:

Infusion rate

C,, (plasma concentration at steady state) Clearance =

Pharmacodynamic analysis A linear pharmacodynamic model of the form ( E ) = S.C where E =

pharmacodynamic effect (here MAP), S = slope of the least squares regression line, and C = verapamil concentration at the E was used to relate verapamil plasma concentration and drug-induced decrease in MAP. Initial studies in which serial electrocardiogram tracings were made at high speed (200mm s-') to evaluate P-R prolongation as a measure of verapamil- induced A-V conduction delay indicated that drug had no demonstrable effect, even at verapamil concentrations at which MAP was markedly decreased. Therefore, no further attempt was made to use this as an additional pharmacodynamic marker. Comparison in pharmacodynamic response between i.p. and i.v. drug administration was made by analysis of covariance. Comparisons of tissue and plasma concentrations of verapamil and norverapamil among various sacrifice times and between route of drug administration were made by Student's unpaired t-test (equal variance) or by non-parametric Mann-Whitney rank sum test when the variances were unequal as evaluated by Levene's test.

RESULTS

Pharmacokinetics The elimination of verapamil from tissue and plasma after a single i.p.

injection of 10mg kg-' verapamil is shown in Figure 1. Distribution equilibrium was apparently complete by 1 h and elimination was log-linear.

KINETICS AND DYNAMICS OF VERAPAMIL 289

\ \ \ \

c \ L 2 4 6 8 10 12 14 16 18 20 22 24

Hour

E 1.0 - P - E z Q YI .- I- m 1 .- g 0.1

E > D

.01

2 4 6 8 10 12 14 16 18 20 22 24 WOll I I ' ' ' ' ' ' '

Hour

Brain Cerebellum

- 2 4 6

Brain Cortex

- 2 4 6

Hour

Brain Stern

\i- u

2 4 6

Figure 1 . Elimination of verapamil from tissue and plasma after a single i.p. injection of lOmg kg-' verapamil. (2 k S.D., 6 rats sacrificed at each time point.) P: plasma, SM: skeletal muscle, CM: cardiac muscle, LI: liver, LU: lung, RM: renal medulla, RC: renal cortex, PF: perirenal fat,

P(free): concentration in plasma not bound to protein

290

E I c E 5 1.0:

- W

ul ul .- I- m \ - .- E, p 0.1: L W 2 0 z

E. L. TODD AND D. R. ABERNETHY

Table 1. Elimination half-life of verapamil from rat tissue

Tissue tY2 (h)

Plasma 1.54 Plamsa (free) 1.54 Lung 1.63 Renal medulla 1.81 Renal cortex 1.83 Liver 1.87 Cardiac muscle 1.94 Skeletal muscle 2.00 Perirenal fat 2.02 Brain stem 1.94 Cerebellum 2.23 Cerebral cortex 2.18

Elimination half-life was similar for all tissues and plasma as shown in Table 1. Norverapamil was detectable in all tissues and plasma by l h , and its concentration in each tissue remained relatively constant during the first three sampling times (Figure 2). Norverapamil was not detectable in the 19 and 24 h samples. After i.v. verapamil infusion to steady state (Figure 3), verapamil concentrations in tissue and plasma were similar to those 3 to 5 h after i.p.

1

1

Hour Figure 2. Concentration of norverapamil in tissue and plasma following a single i.p. injection of 10mg kg-' verapamil. (f ? S.D., 6 rats sacrificed for each time point.) P: plasma, SM: skeletal muscle, CM: cardiac muscle, LI: liver, LU: lung, RM: renal medulla, RC: renal cortex, PF:

perirenal fat, P(free): concentration in plasma not bound to protein

KINETICS AND DYNAMICS OF VERAPAMIL 291

1 2 3 4 5

Hour

Figure 3. Mean arterial pressure and plasma concentrations of verapamil in a single rat infused with verapamil 21.7pg min-' for 20 min followed by 3.25p.g min-' for the duration of the

experiment

verapamil administration; however, norverapamil concentrations during steady state verapamil infusion were significantly Cp < 0.01) lower than norverapamil concentrations after i.p. injection of verapamil (Table 2). Steady state plasma clearance of verapamil was 0.695 f 0.1601 h-'. The free verapamil fraction in plasma was similar in rats receiving i.p. injection (2.28 f 0.30 per cent) and rats infused to steady state (2-08 f 0.30 per cent).

Pharmacody namics Verapamil-induced decrease in MAP was similar after i.p. injection and

i.v. infusion (Figure 4). After i.p. verapamil administration, there was a significant correlation between MAP and verapamil concentration in plasma

Table 2. Comparison of verapamil and'norverapamil in tissue at the termination of steady state infusion and 5 h after a single i.p. dose of verapamil

Tissue Verapamil (pg g-' or pg ml-') Norverapamil (pg g-' or pg ml-') 5-h i.p. Steady state i.v. 5-h i.p. Steady state i.v.

Lung Liver Renal cortex Renal medulla Skeletal muscle Heart Perirenal fat Cerebellum Cerebral cortex Brain stem Plasma

4.28k 1.51 1.04 f 0.53 1.17 f 0.73 1.02 k 0.61 0.23 f 0.06 0.51 f 0.20 0.66 k 0-31 0.05 f 0.02 0.04 f 0.02 0.07 f 0.03 0.27 k 0.10

7.64 f 2.15 1.51 f 0.57 2.26 f 0.62 2-17 k 0.53 0.38 f 0.11 1-07 k 0.33 1.25 f 0.77 0.06 k 0.03 0.06 k 0.04 0.07 f 0.05 0.29 f 0.07

3.16 f 1.09 1.17 & 0.63 0.71 f 0.44 0.58 f 0.37 0.08 f 0.03 0.22 f 0.09

0.013 f 0.009 0.017 k 0.01 0.027 f 0.028 0.16 k 0.09

ND

0.72 f 0.19 0.45 f 0.20 0.25 f 0.11 0.22 f 0.08 0-04 f 0.009 0.11 f 0.04 0.04 f 0.02

0.015 k 0.004 0.013 f 0,007 0.021 f 0-006 0.026 f 0.009

292 E. L. TODD AND D. R . ABERNETHY

a s I 6o

40 ail 20 O O 1 5

T T 12.4

Hours after Ip Injection Hours after lv lnfuslon

Figure 4. Mean arterial pressure and plasma verapamil concentration following i .p. injection of lOmg kg-l verapamil (6 rats sacrificed at each time point) and i.v. infusion of 2 1 . 7 ~ g min-' verapamil for 20 min followed by an infusion of 3.25 pg min-l for 2-4 h (n = 7 rats, P ? S.D.)

( r = -0-75; p < 0-Ol), and between MAP and verapamil concentration in cardiac muscle ( r = -0-82; p < 0.01). Correlation remained significant but was weaker between MAP and free (not bound to plasma proteins) verapamil concentration (r = -0.59; p < 0.01). Comparison of the slope of the linear pharmacodynamic model relating verapamil plasma concentration and MAP plotted against verapamil concentration for individual animals 1, 3, and 5 h after i.p. and i.v. verapamil administration showed no difference in the slopes of the individual regression lines by analysis of covariance (Figure 4). The verapamil-induced decrease in MAP continued over the course of the steady state infusion and was not accentuated or attenuated as a function of infusion duration (Figure 3).

Tissue:plasma distribution ratio The tissue:plasma distribution ratio for both verapamil and norverapamil in

each specific tissue did not differ among the animals sacrificed 1,3 or 5 h after i.p. verapamil injection (p < 0.05). However, when distribution ratios were compared between animals receiving i.v. infusion or i.p. injection, the tissue:plasma distribution ratio was significantly greater for both verapamil (Figure 5) and norverapamil (Figure 6) after i.v. infusion than after i.p. injection, with the exceptions of verapamil in brain and perirenal fat. Therefore, both verapamil and norverapamil were distributed more extensively into tissue after steady state i.v. infusion than after i.p. administration.

KINETICS AND DYNAMICS OF VERAPAMIL

" 4 0 -

E! B

i W

-

293

s E 8 E

a 20 . - %

cp

D Verapamll, I.P.

0 Verapamll, I.v. lnfurlon

**

LUIP LllP RClP RMlP CMlP PFlP SMlP CBlP CXlP 0SlP

Figure 5. Comparison of tissueiplasma verapamil distribution ratio following i.p. injection (n = 30) or i.v. infusion ( n = 7) of verapamil ( * p < 0.05; ' * p < 0.01). P: plasma, SM: skeletal muscle, CM: cardiac muscle, LI: liver, LU: lung, RM: renal medulla, RC: renal cortex, PF: perirenal fat,

P(free): concentration in plasma not bound to protein

Verapamll, I.P.

Verapamll, I.v. lnfuslon

Figure 6 . Comparison of tissue/plasma norverapamil distribution ratio following i.p. injection (n=30) or i.v. infusion (n =7) of verapamil (*p<O.OS; **p<0.01). P: plasma. SM: skeletal muscle, CM: cardiac muscle, LI: liver, LU: lung, RM: renal medulla, RC: renal cortex, PF:

perirenal fat, P(free): concentration in plasma not bound to protein

294 E. L. TODD AND D . R . ABERNETHY

DISCUSSION

Tissue distribution The present study has characterized the tissue distribution of verapamil and

norverapamil after i.p. administration and i.v. infusion of verapamil in Sprague-Dawley rats. Verapamil and norverapamil tissue distribution showed marked organ specificity (LU B RC = RM = LI = PF = CM > P, SM > CB = CX = BS). These relationships did not appear to be well related to organ blood flow or tissue since skeletal muscle, a high flow organ, had lower verapamil concentration than perirenal fat. The brain regions examined, presumably both high blood flow and with high lipid content, had the lowest verapamil and norverapamil concentrations of all tissues examined. The marked concentration of verapamil into lung and minimal concentration into fat is similar to that seen for other basic lipophilic compounds in Y ~ Y O . ' ( ~ ~ ~ Although lipophilicity has been shown to be an important determinant of the relative distribution into a tissue among a series of similar compound^,'"^^ this and other work"'.' 1 * 1 5 3 ' 6 support the importance of physicochemical and biological properties other than tissue or drug lipophilicity as determinants of tissue distribution.

Pharmacodynamic effect Much work has been done to correlate verapamil plasma concentration to

its pharmacodynamic effects on heart rate, P-R interval, and blood pressure in animals and humans.3.4326*27 Reports of correlations of pharmacodynamic effect with verapamil concentrations in cardiac tissue and plasma in animals have been variable because of concomitant haemodynamic and cardiovascu- lar interactions by anaesthetic agents in many studies. l 7 The present work demonstrates highly significant correlations between plasma and cardiac muscle verapamil concentration and verapamil-induced decrease in MAP in the conscious rat, indicating that MAP provides a pharmacodynamic marker of verapamil plasma concentration after acute single-dose i.p. or short-term i.v. verapamil infusion in this animal model. Verapamil-induced effects on P-R interval and heart rate were evaluated in some animals but, using the rat as an animal model, were found to be unchanged as has been demonstrated previoulsy.18 Norverapamil could not be demonstrated to have additive pharmacodynamic activity in this model. After i.p. doses, changes in MAP clearly followed verapamil concentration and at time points when norverapa- mil concentration was a significant proportion of the verapamil concentra- tion, adding total norverapamil or a fraction of the total made the correlation coefficient between drug concentration and MAP decrease as compared to when only verapamil concentration was used. Since appreciable concentra- tions of norverapamil were not detected after i.v. infusion, potential pharmacodynamic effect of norverapamil could not be evaluated. These findings are consistent with the dog model, in which direct administration of norverapamil had no effect on MAP. l 9

KINETICS AND DYNAMICS OF VERAPAMIL 295

Tissue distribution and pharmacodynamic effect: dependence on route of administration

Electrocardiographic P-R interval prolongation, used as a rneasure of AV nodal conduction delay, has been shown in humans to be much less at a given verapamil plasma concentration after oral verapamil than after i.v. administration.3 Mechanism for this phenomenon is at least in part related to stereoselective first-pass clearance, with the pharmacologically more active (-)-verapamil undergoing more extensive first-pass extraction and having higher clearance than ( +)-verapamil.20*2'

Another potential mechanism for such a finding would be variation in target organ concentrations of verapamil and norverapamil with different routes of verapamil administration which Hamann et al.' evaluated in preliminary studies. However, the differences found in patterns of verapamil distribution after i.p. injection in rats and i.v. infusion in dogs were complicated, as the authors discuss, by the problems associated with interspecies variations in drug metabolism.22 The present data demonstrate that the extent of distribution of verapamil and norverapamil is greater into many tissues compared to plasma after i.v. infusion than after i.p. administration; however, the relative pattern of distribution among tissues is similar between i.p. and i.v. administration. Therefore, if i.p. administration in the rat can be considered similar to oral administration in man, this increased tissue distribution after i.v. administration may also contribute to the increased pharmacodynamic effect seen after i.v. administration as compared to oral administration. In this study we evaluated single i.p. doses to a steady state infusion rather than i.v. bolus administration, since we wished to evaluate steady state clearance and the possibility of time-related changes in the plasma concentration-pharmacodynamic effect relationship. Therefore, conditions of administration (single dose i.p. versus steady state i.v. infusion) are not identical and data interpretation must be made with consideration of that potential limitation. Since we found AV nodal conduction delay not to be a useful pharmacodynamic marker for verapamil in the rat, we were unable to evaluate the pharmacodynamic consequences of this increased tissue distribution directly. As the MAP-plasma verapamil concentration relationship was no different between i.v. and i.p. administra- tion, either the effector compartment related to verapamil-induced decrease in MAP (i.e. vascular smooth muscle) has verapamil concentrations similar to those in the intravascular compartment, or all verapamil-induced pharma- codynamic effects are not equally stereoselective. Supporting the latter possibility, (-)-verapamil has been demonstrated in other animal models to be only 2.2 times more effective than (+)-verapamil in decreasing MAP, while verapamil-induced AV nodel conduction delay is ten times more sensitive to the (-)-isomer than to the (+)-isomer.23 Unfortunately we were unable to obtain sufficient vascular smooth muscle tissue for tissue drug and metabolite measurements.

296 E. L. TODD AND D. R. ABERNETHY

Mechanisms potentially explaining the dependence of the tissue distribu- tion ratio on route of administration include differences in plasma protein binding which depend on route of drug administration, stereoselective presystemic elimination of the more extensively distributed (-)-isomer after oral dosing,20-21 alteration in tissue distribution of drug due to increased concentrations of norverapamil or other metabolites after oral and i.p. adrninistrati~n,~ and drug-induced haemodynamic changes including perfu- sion of different organ beds that differed between routes of a d m i n i ~ t r a t i o n . ~ ~ . ~ ~ The present work demonstrates that plasma protein binding of (+)-verapamil does not differ with route of drug administration; however, we cannot exclude alteration in binding of specific stereoisomers. The other mechanisms cannot be excluded by the present data, and they may contribute to the observed dependence of distribution ratio on route of administration. If norverapamil or other metabolites compete with verapamil for plasma protein or tissue binding, then the increased norverapamil tissue concentration observed after i.p. verapamil administration may lead to altered partitioning of verapamil into tissue compared to plasma than after i.v. administration. This seems unlikely due to the very low concentrations of metabolites achieved in these studies and the presumed non-specific nature of the tissue binding. In vivo total volume of distribution has been demonstrated to be greater for (-)-verapamil than for ( +)-verapamil.20 If this is reflecting distribution into specific tissues, then following i.v. administration, more (-)+erapamil will be available for distribution into tissues. Finally, acute verapamil administration has been associated with transiently increased hepatic and renal blood flow, which returns to baseline values with continued drug admin i~ t r a t ion .~~ After administration of another calcium antagonist, nitrendipine, acute alterations in flow to iliac and splanchnic beds were noted.25 These acute changes in organ perfusion, which may return to baseline during chronic exposure, could also contribute to the alteration in plasma to tissue distribution noted here. The relative contributions of the latter mechanisms to the observed dependency of distribution ratio on route of administration cannot be clearly assessed.

In summary, an animal model has been described which exhibits good correlation between verapamil-induced decrease in MAP and pharmacokine- tics after i.v. and i.p. verapamil administration. The extent of distribution of verapamil and norverapamil into tissue from plasma has been shown to depend on route of drug administration with increased distribution into tissue occurring after i.v. administration. For this relatively lipophilic drug, tissue concentration in different organs is not well related to either ogan lipid content or organ blood flow. Drug physiochemical and organ physiologic characteristics which are major determinants for specific organ distribution of verapamil remain to be defined.

KINETICS A N D DYNAMICS OF VERAPAMIL 297

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the technical assistance of Maya Sadhukhan and the support of Dr Jerry R. Mitchell. This work is supported in part by Grants AM 33479 and GM 34120 frcm the United States Public Health Services.

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