Verapamil Kinetics Research Articles

(R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus.

BackgroundIncreased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.Methods(R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).ResultsAll data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.ConclusionsP-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.

Pharmacoresistance in Epilepsy: A Pilot PET Study with the P‐Glycoprotein Substrate R‐[11C]verapamil

Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[(11)C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[(11)C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus. Among different VOIs, radioactivity was highest in the choroid plexus. The hippocampal VOI could not be used for data analysis because it was contaminated by spill-in of radioactivity from the adjacent choroid plexus. In several other temporal lobe regions that are known to be involved in seizure generation and propagation ipsilateral influx rate constants K(1) and efflux rate constants k(2) of R-[(11)C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus (K(1), range: -3.8% to +22.3%; k(2), range: -2.3% to +43.9%), amygdala (K(1), range: -20.6% to +31.3%; k(2), range: -18.0% to +38.9%), medial anterior temporal lobe (K(1), range: -8.3% to +14.5%; k(2), range: -14.5% to +31.0%) and lateral anterior temporal lobe (K(1), range: -20.7% to +16.8%; k(2), range: -24.4% to +22.6%). In contrast to temporal lobe VOIs, asymmetries were minimal in a region presumably not involved in epileptogenesis located outside the temporal lobe (superior parietal gyrus, K(1), range: -3.7% to +4.5%; k(2), range: -4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux (k(2)) increases were more pronounced than ipsilateral influx (K(1)) increases, which resulted in ipsilateral reductions (10%-26%) of R-[(11)C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K(1), k(2) and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p > 0.05, Wilcoxon matched pairs test). Even though we failed to detect statistically significant differences in R-[(11)C]verapamil model parameters between epileptogenic and nonepileptogenic brain regions, it cannot be excluded from our pilot data in a small sample size of patients that regionally enhanced P-gp activity might contribute to drug resistance in some patients with temporal lobe epilepsy.

Quantitative assessment of P-glycoprotein function in the rat blood–brain barrier by distribution volume of [11C]verapamil measured with PET

The blood–brain barrier (BBB) is a functional barrier that hampers the delivery of various drugs to the brain by its physicoanatomical properties and by the presence of ATP-driven drug efflux pumps, such as P-glycoprotein (P-gp). The aims of this study were (1) to study whether the distribution volume (DV) is useful for quantification of (labeled) P-gp substrate kinetics over the BBB and (2) to study how brain DV is affected by P-gp modulation. We measured the kinetics of the P-gp substrate [11C]verapamil (0.1 mg/kg) in rat brains using positron emission tomography (PET) and arterial blood sampling. Cyclosporin A (CsA) at 0, 10, 15, 25, 35, and 50 mg/kg of body weight was used as a P-gp modulator. The [11C]verapamil kinetics were very well described by DV, computed by noncompartmental Logan analysis. Logan analysis resulted in excellent fits of dynamic PET data, revealing the reversible behavior of [11C]verapamil and its associated DV. The DV in unmodulated rats was 0.65 ml/ml ± 0.23 (mean ± SD). After modulation with 10, 15, 25, 35, and 50 mg/kg of CsA, DV values increased to 0.82 ± 0.06, 1.04 ± 0.20, 2.85 ± 0.51, 2.91 ± 0.64, and 3.77 ± 1.23, respectively. The [11C]Verapamil kinetics were saturable at modulation levels above 25 mg/kg of CsA. The data fitted well by a four-parameter Hill plot (R2 = 0.79). In conclusion, the DV of [11C]verapamil is a valid and potent tool to measure the kinetics of (labeled) P-gp substrates in vivo at the BBB. The brain DV of [11C]verapamil increases dose dependently by P-gp modulation. Quantitative insight into in vivo P-gp modulation may be a promising step toward assessment of P-gp substrate delivery to human brains.

Effect of cimetidine on verapamil disposition.

The effects of multiple doses of cimetidine on single-dose verapamil kinetics were studied in nine healthy men. Baseline hepatic blood flow was estimated by indocyanine green elimination on day 1. On day 2, the subjects received verapamil, 10 mg iv, after which the plasma concentration-time profile was determined. After a 2-day washout, cimetidine, 300 mg, was taken by mouth four times a day for 5 days. The indocyanine green study was repeated on day 9 and verapamil was taken on day 10. Cimetidine reduced verapamil clearance by 21% and increased the elimination t1/2 by 50%. The volume of distribution at steady state did not change. Cimetidine increased hepatic blood flow in some subjects, while decreasing it in others. There was no correlation between individual changes in verapamil clearance and hepatic blood flow. These data indicate that cimetidine reduces verapamil clearance by mechanism(s) other than a change in hepatic blood flow or volume of distribution.

Influence of cimetidine on verapamil kinetics and dynamics.

The kinetics and dynamics of single doses of verapamil (10 mg iv and 120 mg by mouth) were followed in eight subjects on oral cimetidine (300 mg every 6 hr) and placebo. Cimetidine had no effect on intravenous verapamil kinetics but induced a significant rise in oral verapamil bioavailability. Other kinetic parameters of verapamil were not altered by cimetidine. Verapamil induced a significant slowing of atrioventricular conduction (39.8 msec intravenous; 24.5 msec oral). Although there was a significant increase in oral verapamil bioavailability, after cimetidine, there was no change in PR interval prolongation with either oral or intravenous verapamil. Our data demonstrate the importance of correlating measurable drug effects with kinetic studies when drug interactions are studied and their clinical significance is assessed.

The Pharmacology of Verapamil. IV. Kinetic and Dynamic Effects after Single Intravenous and Oral Doses

Kinetics and plasma level-effect correlates for verapamil were studied in 20 normal young men (mean age, 25.2 +/- 3.6 yr). In a randomized four-way crossover design, each subject received 10 mg verapamil intravenously and 80, 120, and 160 mg in single oral doses. Changes in heart rate, blood pressure, and PR interval were evaluated serially after each dose; plasma concentrations of verapamil were measured by high-performance liquid chromatography. Levels of the active metabolite norverapamil were determined in five subjects. Verapamil kinetics were the same after intravenous and oral doses: elimination half-life (t 1/2 beta) ranged from 3.7 to 4.8 hr, apparent volume of distribution varied between 4.2 and 5.5 l/kg, and total clearance was 0.71 to 0.86 l/hr/kg. Verapamil bioavailability was not dose dependent and averaged 19.4%. Norverapamil, found only after oral doses, had a t 2/2 beta and maximum concentration much the same as the parent drug. There were only minor effects on heart rate and blood pressure after single doses. Hysteresis analysis showed that plasma verapamil concentrations after intravenous doses correlated with PR interval prolongation only after a 30-min lag time; there was no lag after oral doses. There was considerable interindividual variation in sensitivity to verapamil's effect on atrioventricular conduction; subjects with longer control PR interval values tended to have greater prolongation of effect than those with shorter intervals. Verapamil was well tolerated in both dosage forms by all subjects.

Verapamil kinetics in normal subjects and patients with coronary artery spasm.

Verapamil kinetics after intravenous and single and long-term oral dosing were studied in 12 patients with coronary artery spasm and four normal subjects. The decline in plasma concentration after intravenous doses was described by triexponential decay equation, with a terminal half-life (t1/2) of 5 hr. After a single oral dose the bioavailability was only 24%, probably because of the first-pass metabolism. During long-term oral doses of 80 mg every 6 hr, mean peak and trough concentrations were 255 +/- 90 and 105 +/- 38 ng/ml, and mean time at which peak concentration occurred was 1.2 +/- 0.5 hr. Norverapamil, the major active metabolite of verapamil, cumulated during oral dosing and may account for a small proportion of the overall pharmacologic effect. Mean elimination t1/2 during long-term oral dosing was longer than after a single dose (9.6 and 5.7 hr, P less than 0.05). Also, during long-term dosing the area under the curve was more than double that of a single dose, and the apparent oral clearance fell from 4.2 to 1.8 l/min (P less than 0.01). These changes may partly be explained by reduction in presystemic metabolism during long-term therapy. Kinetic predictions based on single doses will not give reliable estimates for long-term oral dosage. Less frequent dose schedule may be possible for prolonged therapy.

Influence of meso‐caval shunt surgery on verapamil kinetics, bioavailability and response.

British Journal of Clinical PharmacologyVolume 10, Issue 5 p. 527-530 Free Access Influence of meso-caval shunt surgery on verapamil kinetics, bioavailability and response. M Eichelbaum, M EichelbaumSearch for more papers by this authorM Albrecht, M AlbrechtSearch for more papers by this authorG Kliems, G KliemsSearch for more papers by this authorK Schafer, K SchaferSearch for more papers by this authorA Somogyi, A SomogyiSearch for more papers by this author M Eichelbaum, M EichelbaumSearch for more papers by this authorM Albrecht, M AlbrechtSearch for more papers by this authorG Kliems, G KliemsSearch for more papers by this authorK Schafer, K SchaferSearch for more papers by this authorA Somogyi, A SomogyiSearch for more papers by this author First published: November 1980 https://doi.org/10.1111/j.1365-2125.1980.tb01800.xCitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References EICHELBAUM, M. & SPANNBRUCKER, N. (1977). Rapid and sensitive method for the determination of antipyrine in biological fluids by high pressure liquid chromatography. J. Chromatogr., 140, 288– 292. GEORGE, C.F. (1979). Drug kinetics and hepatic blood flow. Clin. Pharmacokin., 4, 433– 448. GUGLER, R., LAIN, P. & AZARNOFF, D.L. (1975). Effect of portacaval shunt on the disposition of drugs with and without first-pass effect. J. Pharmac. exp. Ther., 195, 416– 423. HUET, M., Le LORIER, J., POMIER, G. & MARLEAN, D. (1979). Bioavailability of lignocaine in normal volunteers and cirrhotic patients. Clin. Pharmac. Ther., 25, 230. METZLER, C. (1969). A user's manual for Nonlin. Technical Report 7292/69/7292/005, Kalamazoo, Michigan: Up-john Company. NEAL, E.A., MEFFIN, P.J. GREGORY, P.B. & BLASCHKE, T.F. (1979). Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology, 77, 96– 102. SCHOMERUS, M., SPIEGELHALDER, B., STIEREN, B. & EICHELBAUM, M. (1976). Physiological disposition of verapamil in man. Cardiovascular Res., 10, 605– 612. SHAND, D.G. & RANGNO, R.G. (1972). The disposition of propranolol. 1. Elimination during oral absorption in man. Pharmacology, 7, 159– 168. SPIEGELHALDER, B. & M. EICHELBAUM (1977). Determination of verapamil in human plasma by mass fragmentography using stable-labelled verapamil as internal standard. Arzneimittel-Forsch., 27, 94– 97. WAGNER, J.G. (1976). Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J. Pharmacokinet. Biopharmac., 4, 443– 467. Citing Literature Volume10, Issue5November 1980Pages 527-530 ReferencesRelatedInformation