The pharmacokinetics of trinitroglycerin and its metabolites in patients with chronic stable angina

Abstract

Aims

To study the pharmacokinetics of trinitroglycerin (GTN) and its four metabolites in angina patients during their transient use of transdermal GTN tape following intravenous administration of GTN.

Methods

Four patients received a GTN tape following intravenous administration of 0.1 µg kg⁻¹ min⁻¹ GTN, and the other four patients received two GTN tapes following intravenous administration of 0.2 µg kg⁻¹ min⁻¹ GTN.

Results

Plasma concentrations of GTN in both groups during tape application showed a slight decrease for the hour after the application of the tape and then were con- stant for 24 h. In contrast, the concentrations of dinitroglycerins (GDNs) and mononitroglycerins (GMNs) depended on the duration of previous intravenous administration of GTN. Neither significant cardiovascular changes nor undesirable complications were observed during the study.

Conclusions

The results suggest that appropriate replacement of intravenous GTN administration with transdermal tape application could maintain a therapeutic GTN level.

Introduction

The use of trinitroglycerin (GTN) is widespread in hospitalized patients. In the intensive care setting, we routinely administer GTN intravenously to patients who have coronary artery disease. When such patients are stable and are to be transferred to the general ward, GTN tapes are frequently substituted for intravenous GTN because of therapeutic convenience. A pharmacokinetic study comparing these two forms of therapy, however, has not yet been undertaken because of the difficulty in measuring GTN and its metabolites [1]. The goal of this study was to continuously monitor cardiovascular parameters and plasma concentration of GTN and its four metabolites, 1,2-glyceryl dinitrate (1,2-GDN) 1,3-glyceryl dinitrate (1,3-GDN), 1-glyceryl mononitrite (1-GMN), and 2-glyceryl mononitrite (2-GMN), for 24 h during the application of GTN tapes. Two different quantities of GTN in the tapes were compared and the tapes were applied after the patients had received intravenous infusions of GTN.

Methods

Eight patients (six males and two females, mean age 66.4 years (range, 49–81 years), mean body weight 52 kg (range, 41–66 kg)] with chronic stable angina responsive to sublingual nitroglycerin were studied during their stay in the intensive care unit (ICU). The patients were divided randomly into two groups. Based on the clinical usage in our ICU setting, four patients received one GTN tape (Vasolator tape® from Sanwa Kagaku Kenkyusyo Co. Ltd, Nagoya, Japan. The tape contained 27 mg of GTN with a release rate of about 5 mg 24 h⁻¹) 30 min prior to termination of the intravenous administration of 0.1 µg kg⁻¹ min⁻¹ GTN (One tape group, patients number 1–4). The other four received a double dose, two tapes 30 min prior to the termination of an infusion of 0.2 µg kg⁻¹ min⁻¹ GTN (Two tape group, patients number 5–8). The plasma concentrations of GTN, GDNs, and GMNs were measured 0, 0.5 (the end point of intravenous administration), 1, 3, 6, 12, and 24 h after the application of GTN tapes. During the study all patients were monitored with continuous ECG recording, heart rate and systemic and pulmonary arterial blood pressure. Cardiac output was measured by the thermodilution method. The cardiac function of the all patients remained stable during the study. Blood samples were collected in heparin-coated cooled glass tubes and were immediately centrifuged at 4 °C. Plasma samples were stored at −80 °C until analysed. Plasma concentrations of GTN and its metabolites were determined by gas chromatography according to the method of Han et al. with modification [1]. Briefly, 1 ml of plasma sample was mixed with 50 µl of internal standard solution (150 ng ml⁻¹o-iodobenzyl alcohol) and extracted with ethyl acetate. The organic phase was applied to a short column and eluted using 4 ml of ethyl acetate. The elutant was evaporated by rotary vacuum evaporator and dissolved with 200 µl of n-hexane. One µl of the n-hexane was injected into a gas chromatograph for the simultaneous measurement of GTN and four metabolites. The lower limit of quantification was 0.05 ng ml⁻¹ for GTN, 0.2 ng ml⁻¹ for GDNs, and 1.0 ng ml⁻¹ for GMNs, respectively.

The patients or their family gave informed consent to participate in the study. The protocol was approved by the Ethics Committee at the University hospital. Four patients (numbers 1, 4, 6 and 7) received intravenous GTN for 12–24 h prior to the study because of their clinical demands, and the other four for 1–2 h because they became participants in the study.

The data are expressed as mean and s.d. One-way analysis of variance was used for the statistical analysis of circulatory parameters and levels of GTN and its metabolites. Dunnett's procedure was used for the posthoc multicomparison analysis. We regarded the data as statistically significant with a P value of < 0.05.

Results

The time courses of GTN and its metabolites concentrations are summarized in Table 1 and Table 2. In the one tape group, the concentrations of GTN were initially 1.14 ± 0.13 ng ml⁻¹ (0 h, time for tape application), then decreased after the termination of intravenous administration and kept relatively constant for 24 h thereafter. Although the same trends were observed in the two tapes group, the concentrations of GTN and its metabolites were significantly higher (2.5–4 times) than the one tape group. The clearances of GTN calculated as the intravenous administration rate (ng min⁻¹) divided by the concentration (ng ml⁻¹) at 0 h were 4.4 l min⁻¹ for the one tape group and 2.6 l min⁻¹ for the two tapes group. There was a small variability of GTN concentrations regardless of the duration of the intravenous infusion. While the concentrations of GDNs and GMNs were more variable, there was a correlation with the duration of intravenous administration, which resulted in higher con-centrations of GDN and GMN in patient numbers 1, 4, 6 and 7. No significant cardiovascular changes or subjective aspect of the ischaemia were observed during the study. Data for cardiac output were 3.51 ± 0.57 l min⁻¹ m⁻² (0 h) and 2.96 ± 0.45 l min⁻¹ m⁻² (24 h) in the one tape group, and 2.65 ± 0.63 l min⁻¹ m⁻² (0 h) and 3.15 ± 0.61 l min⁻¹ m⁻² (24 h) in the two tape groups. There were no significant differences in the values for cardiac output between the two groups. Pulmonary wedge pressures and arterial blood gas analyses also documented that no significant haemodynamic changes occurred during the study and all the patients had no episodes of angina attack or ST depressions in ECG monitoring.

Table 1.

Concentrations of GTN, GDNs and GMNs in the one tape group.

	GTN concentration (ng ml−1)
Time(h)	No.1	No.2	No.3	No.4	Mean	s.d.
0	1.26	0.95	1.16	1.19	1.14	0.13
0.5	1.36	0.71	0.92	1.66	1.16	0.43
1	0.67	0.57	0.53	0.68	0.61*	0.07
3	0.50	0.41	0.62	0.69	0.55*	0.12
6	0.55	0.40	0.97	0.75	0.67*	0.25
12	0.58	0.40	0.73	0.47	0.54*	0.14
24	0.50	0.35	0.31	0.32	0.37*	0.09
CLtot(l min−1)	4.0	5.3	4.3	4.2	4.4	0.57

	GDN concentration(ng ml−1)
Time(h)	No.1 1,2-GDN	1,3-GDN	No.2 1,2-GDN	1,3-GDN	No.3 1,2-GDN	1,3-GDN	No.4 1,2-GDN	1,3-GDN	Mean 1,2-GDN	Mean 1,3-GDN	s.d. 1,2-GDN	s.d. 1,3-GDN
0	3.81	0.39	1.20	0.60	2.19	0.32	1.50	0.93	2.18	0.56	1.17	0.27
0.5	4.62	0.42	1.71	0.79	2.09	0.48	2.24	1.20	2.67	0.72	1.32	0.36
1	3.29	0.23	1.55	0.97	1.65	0.48	1.52	0.98	2.00	0.66	0.86	0.37
3	1.97	0.23	1.16	0.75	1.47	0.43	1.32	0.88	1.48	0.57	0.35	0.30
6	1.38	0.21	0.57	0.41	1.94	0.42	1.31	0.71	1.30	0.44	0.56	0.20
12	1.70	0.20	0.55	0.49	1.76	0.39	0.83	0.53	1.21	0.40	0.61	0.15
24	1.27	0.20	0.49	0.50	0.91	0.29	0.53	0.42	0.80*	0.35	0.37	0.13

	GMN concentration(ng ml−1)
Time(h)	No.1 1-GMN	2-GMN	No.2 1-GMN	2-GMN	No.3 1-GMN	2-GMN	No.4 1-GMN	2-GMN	Mean 1-GMN	Mean 2-GMN	s.d. 1-GMN	s.d. 2-GMN
0	9.36	68.65	1.55	8.81	1.49	4.78	4.55	21.71	4.24	25.99	3.70	29.34
0.5	10.45	78.33	2.53	11.61	1.81	5.71	4.92	21.54	4.93	29.30	3.92	33.34
1	7.95	64.34	1.18	7.93	1.95	7.15	4.15	18.94	3.81	24.59	3.03	27.04
3	6.50	56.31	4.03	7.33	2.18	8.82	4.71	21.17	4.36	23.41	1.79	22.79
6	2.76	33.57	5.40	7.07	2.20	9.40	3.52	18.42	3.47	17.12	1.40	12.01
12	2.45	24.55	3.80	6.35	2.81	12.49	3.45	11.98	3.13	13.84	0.61	7.66
24	1.97	13.00	3.53	6.65	2.81	10.32	3.80	9.05	3.03	9.76	0.82	2.65

^*P < 0.05 vs Time 0, CLtot (l min⁻¹): Total clearance.

^*P < 0.05 vs Time 0.

No significant difference was detected.

Table 2.

Concentrations of GTN, GDNs and GMNs in the two tape group.

	GTN concentration (ng ml−1)
Time(h)	No.5	No.6	No.7	No.8	Mean	s.d.
0	4.40	5.17	3.12	3.56	3.99?	0.81
0.5	4.50	7.85	4.69	2.58	4.71	1.94
1	1.47	3.31	2.10	0.83	1.84*	0.93
3	1.94	4.26	1.67	0.86	2.04*	1.30
6	1.57	3.52	1.54	0.85	1.76*	1.03
12	1.53	2.71	1.11	0.78	1.45*	0.75
24	1.08	2.36	0.88	0.58	1.15*	0.70
CLtot(l min−1)	2.3	1.9	3.2	2.8	2.6	0.60

	GDN concentration(ng ml−1)
Time(h)	No.5 1,2-GDN	1,3-GDN	No.6 1,2-GDN	1,3-GDN	No.7 1,2-GDN	1,3-GDN	No.8 1,2-GDN	1,3-GDN	Mean 1,2-GDN	Mean 1,3-GDN	s.d. 1,2-GDN	s.d. 1,3-GDN
0	4.94	1.24	8.82	2.80	10.48	5.31	3.49	1.18	6.93?	2.63	3.26	1.94
0.5	6.42	1.54	9.50	2.56	9.14	4.44	3.32	1.36	7.10	2.48	2.87	1.41
1	4.45	1.54	8.89	2.50	7.60	4.05	2.36	0.90	5.83	2.25	2.97	1.37
3	4.19	1.34	7.40	2.87	4.63	2.53	1.64	0.96	4.47	1.93	3.36	0.92
6	3.40	1.45	6.78	2.33	2.84	2.13	1.54	0.87	3.64	1.69	2.23	0.67
12	3.24	1.55	4.72	1.58	1.71	1.43	1.65	0.96	2.83*	1.38	1.46	0.29
24	1.87	1.50	4.03	1.68	1.04	1.40	1.12	0.81	2.02*	1.35	1.40	0.38

	GMN concentration(ng ml−1)
Time(h)	No.5 1-GMN	2-GMN	No.6 1-GMN	2-GMN	No.7 1-GMN	2-GMN	No.8 1-GMN	2-GMN	Mean 1-GMN	Mean 2-GMN	s.d. 1-GMN	s.d. 2-GMN
0	3.31	9.32	13.64	103.49	23.58	104.47	3.96	3.92	11.12	55.30	9.55	56.25
0.5	5.73	13.93	11.22	92.31	25.16	125.99	4.05	4.97	11.54	59.30	9.58	59.29
1	5.50	17.72	13.61	89.91	23.87	106.40	2.96	4.85	11.49	54.72	9.42	50.87
3	6.65	22.46	12.85	93.16	21.75	89.03	4.52	7.29	11.44	52.98	7.73	44.47
6	5.36	16.43	10.40	79.17	20.76	78.57	4.24	8.82	10.19	45.75	7.54	38.37
12	4.79	26.22	7.89	55.55	13.75	39.66	4.72	9.29	7.79	32.68	4.24	19.67
24	7.24	20.02	3.64	31.06	5.84	21.99	5.00	12.17	5.43	21.31	1.51	7.76

^*P < 0.05 vs Time 0

^?P < 0.05 vs Time 0 of one tape group, CLtot(l min⁻¹): Total clearance.

^*P < 0.05 vs Time 0

^?P < 0.05 vs Time 0 of the one tape group.

No significant difference was detected.

Discussion

The substitution of transdermal tape for the intravenous GTN infusions maintained plasma concentration of GTN over 24 h and did not cause adverse cardiovascular effects in any patients studied. Although there was significant variability in the concentrations of GDNs and GMNs among the patients, GTN concentrations correlated with the dose of the intravenous and transdermal administration. This result is reasonable considering the rapid turnover rate of GTN and slower turnover rates of its metabolites. The concentrations of GTN and its metabolites in the two tapes group were much higher (2.5–4 times) than those of the one tape group. The difference was probably due to the decrease of the total clearance of GTN when the dose was doubled. The concentrations of 1,2-GDN were always higher than that of 1,3-GDN and the concentrations of 2-GMN were higher than that of 1-GMN in both groups. This trend confirmed the previously published data by Han et al.[1].

A major benefit of the transdermal administration of GTN is that it avoids first-pass inactivation by the liver. In addition, the problems of variable drug absorption and fluctuating plasma concentrations caused by GTN ointment were overcome by the transdermal patch or tape system. The continuous use of transdermal GTN tape can still lead to nitrate tolerance [2]. Recent data suggest that the intermittent application of transdermal GTN may be associated with decreased exercise capacity as well as the development of unstable angina when the tape is not applied [3]. Thus, a reasonable approach may be to apply the transdermal GTN tape only during the daytime then the patients are active and awake.

In conclusion, this study documented the pharmacokinetics of GTN and its metabolite during the application of transdermal GTN after GTN infusions in patients with chronic stable angina. The result suggested that the transdermal application of GTN would maintain GTN concentration adequately following intravenous administration of GTN.