Enhancement of Theophylline Clearance by Oral Albuterol* Yona Amitai, M.D.; joseph Glustein, M.D.; and Simon Godfrey, M.D., Ph.D. The possible effect of a1buterol on theophylline clearance was studied in ten adult volunteen. Subjects received intravenous aminophylline loading dose (5.6 mWkg), with oral a1buterol (4 mg every 6 h), or inhaled a1buterol (200 fLg every 6 h), or alone (control). Theophylline levels were determined for II-h periods. Theophylline clearance and elimination t~ were calculated. Theophylline clearance was signi&cantly higher when given with oral albuterol, in comparison with control (O.83::t 0.05 vs 0.73::t 0.06 mllkgl min, pao = area uDder the curve of serum theophyDine concentrations £rom zero to in&nity; CI dearance; Co estrapolated senun tbeophyUine concentrations at time zero; Ke = elimination rate eonstant; t~=baI£-1ife time
=
=
Ebtients Ten healthy, nonsmoking volunteers (eight male), 23 to 30 years ofage, weighing within 10 percent of their ideal body weight, were selected. They were not taking any medications for the preceding week before entering the stud~ They refrained from alcohol and xanthine-containing food and beverages 48 h prior to and during the study period. Study Protocol Aminophylline (Teva Pharmaceuticals Industry Ltd, Jerusalem, Israel, lot No. 97341), 5.6 mglkg, up to a maximal dose of 400 mg, was infused intravenously over 20 min, on three separate occasions, one week apart. Four of the patients received a dose of 400 mg. On two occasions, the subjects also took either (1) albuterol 4-mg tablets (Glaxo Group Research Ltd, Greenford, UK, lot W0698EA) ingested 1 h before meals, or (2) two puffs of albuterol 100 J.Lg (200 JLg) metered dose inhalation (Glaxo Group Research Ltd, Greenford, UK, lot SOI98GA) at 6-h intervals for 48 h prior to and 12 h after the aminophylline infusion. On the third occasion, the aminophylline infusion was given with no other medications (control). The sequence of oral albuterol, inhaled albuterol, and the control was randomly assigned. Before starting the study, the subjects were instructed how to use metered dose inhalations, and their compliance with oral and inhaled albuterol was checked by measurements of serum albuterol concentrations. For determination of serum theophylline concentrations, blood samples were drawn through an indwelling venous catheter before and at 10 min, I, 2, 4, 6, 8, 10, and 12 h after the aminophylline infusion. For determination of serum albuterol concentrations, additional blood samples were drawn before and at 2, 4, and 6 h after the ingestion or inhalation of albuterol dose given with the aminophylline infusion. Samples were centrifuged and the serum was separated and stored at - OOOC until analyzed. Theophylline assay was performed by the Huorescence polarization immunoassay (TDx, Abbott Laboratories, North Chicago, Ill). The coefficient of variation for theophylline assay was 5.7 percent at 7.0 mgIL and 3.7 percent at 12.0 mgIL during the study period. Albuterol assay was performed by the high performance liquid chromatography (at the laboratories of Bios, Ltd, Bagshot, UK) as previously described.:5 The limit of quantification for the assay was Enhancement of Theophylline Clearance (AmItaJ, Glustein, Godfrey)
Table 1- PMrmtlC01dnetic Parameterl of Theophylline Following lratraveftOUl AmiraophyUirae Loading Alone (Control) and with Oral or lnlaaled Albuterol p Value· Variables
Control
Albuterol
Inhaled Albuterol
CO,mWL AUCo->oo, mg'b/L CI, mllkwmin Elimination tlh, h
8.6±0.3t 99.8±6.4 0.73 ± 0.06 8.1±0.6
8.4±0.3 85.9±4.4 0.83±0.05 7.1±0.3
8.3±0.3 96.8±6.6 0.75±0.05 8.3±0.7
Oral
poral
pinh
>0.1 0.5 >0.1
*p value of comparison between oral albuterol and control (P oral), and between inhaled albuterol and control (P inh). tValues are mean ± SE. *SigniJicant with the Bonferroni correction. 1 nwml, and the calibration range was 1 to 20 nWml. The interassay precision (CV) was 4.8 percent at 20 nwml and 7.9 percent at 1 oW ml; the mean bias were 1.55 and 20.0 percent, respectively.
Phannacokinetic Analysis Pharmacokinetic analysis was done with a noncompartmental model. The following parameters were determined: Co, the extrapolated serum theophylline concentration after the completion of the infusion. The elimination rate constant (ICe) was estimated from the slope of serum concentration time plot by the regression analysis. The elimination half-life (tlh) oftheophylline was calculated as follows: tlh (hours) = 0.693IKe. Clearance values were calculated using the trapezoid rule to determine the area under the curve (AUCo- > 12) from measured serum theophylline concentrations vs time graphs for each individual patient. The extrapolation of AUC to infinity was estimated as follows: AUCo- >00 (mg'hIL) =AUCo- > 12 + C(12)IKe where C(12) is the serum theophylline concentration at 12 h after completion of the infusion. The total body clearance (CI) of theophylline was assumed to be inversely related to the AUC as follows: Total body CI (mJlkwmin) =dose (mg)·O.81AUCo->oo (mg'hIL) where 0.8 re8ects the 80 percent theophylline constituent of aminophylline.
Statistbll Analysis
Paired t test and the linear regression analysis were used as appropriate. The p values of less than 0.05 were considered signi6cant. The Bonferroni correction was used for multiple comparisons. Data are expressed as means ± SE. 10
.
& -..
eft
af
~ -'
.1
= >.
9 8 7 6 5 4
~
•l-
~
t-
•...
.,.•
3
Control Orat atbuterot
0---
=
=
Ebtients Ten healthy, nonsmoking volunteers (eight male), 23 to 30 years ofage, weighing within 10 percent of their ideal body weight, were selected. They were not taking any medications for the preceding week before entering the stud~ They refrained from alcohol and xanthine-containing food and beverages 48 h prior to and during the study period. Study Protocol Aminophylline (Teva Pharmaceuticals Industry Ltd, Jerusalem, Israel, lot No. 97341), 5.6 mglkg, up to a maximal dose of 400 mg, was infused intravenously over 20 min, on three separate occasions, one week apart. Four of the patients received a dose of 400 mg. On two occasions, the subjects also took either (1) albuterol 4-mg tablets (Glaxo Group Research Ltd, Greenford, UK, lot W0698EA) ingested 1 h before meals, or (2) two puffs of albuterol 100 J.Lg (200 JLg) metered dose inhalation (Glaxo Group Research Ltd, Greenford, UK, lot SOI98GA) at 6-h intervals for 48 h prior to and 12 h after the aminophylline infusion. On the third occasion, the aminophylline infusion was given with no other medications (control). The sequence of oral albuterol, inhaled albuterol, and the control was randomly assigned. Before starting the study, the subjects were instructed how to use metered dose inhalations, and their compliance with oral and inhaled albuterol was checked by measurements of serum albuterol concentrations. For determination of serum theophylline concentrations, blood samples were drawn through an indwelling venous catheter before and at 10 min, I, 2, 4, 6, 8, 10, and 12 h after the aminophylline infusion. For determination of serum albuterol concentrations, additional blood samples were drawn before and at 2, 4, and 6 h after the ingestion or inhalation of albuterol dose given with the aminophylline infusion. Samples were centrifuged and the serum was separated and stored at - OOOC until analyzed. Theophylline assay was performed by the Huorescence polarization immunoassay (TDx, Abbott Laboratories, North Chicago, Ill). The coefficient of variation for theophylline assay was 5.7 percent at 7.0 mgIL and 3.7 percent at 12.0 mgIL during the study period. Albuterol assay was performed by the high performance liquid chromatography (at the laboratories of Bios, Ltd, Bagshot, UK) as previously described.:5 The limit of quantification for the assay was Enhancement of Theophylline Clearance (AmItaJ, Glustein, Godfrey)
Table 1- PMrmtlC01dnetic Parameterl of Theophylline Following lratraveftOUl AmiraophyUirae Loading Alone (Control) and with Oral or lnlaaled Albuterol p Value· Variables
Control
Albuterol
Inhaled Albuterol
CO,mWL AUCo->oo, mg'b/L CI, mllkwmin Elimination tlh, h
8.6±0.3t 99.8±6.4 0.73 ± 0.06 8.1±0.6
8.4±0.3 85.9±4.4 0.83±0.05 7.1±0.3
8.3±0.3 96.8±6.6 0.75±0.05 8.3±0.7
Oral
poral
pinh
>0.1 0.5 >0.1
*p value of comparison between oral albuterol and control (P oral), and between inhaled albuterol and control (P inh). tValues are mean ± SE. *SigniJicant with the Bonferroni correction. 1 nwml, and the calibration range was 1 to 20 nWml. The interassay precision (CV) was 4.8 percent at 20 nwml and 7.9 percent at 1 oW ml; the mean bias were 1.55 and 20.0 percent, respectively.
Phannacokinetic Analysis Pharmacokinetic analysis was done with a noncompartmental model. The following parameters were determined: Co, the extrapolated serum theophylline concentration after the completion of the infusion. The elimination rate constant (ICe) was estimated from the slope of serum concentration time plot by the regression analysis. The elimination half-life (tlh) oftheophylline was calculated as follows: tlh (hours) = 0.693IKe. Clearance values were calculated using the trapezoid rule to determine the area under the curve (AUCo- > 12) from measured serum theophylline concentrations vs time graphs for each individual patient. The extrapolation of AUC to infinity was estimated as follows: AUCo- >00 (mg'hIL) =AUCo- > 12 + C(12)IKe where C(12) is the serum theophylline concentration at 12 h after completion of the infusion. The total body clearance (CI) of theophylline was assumed to be inversely related to the AUC as follows: Total body CI (mJlkwmin) =dose (mg)·O.81AUCo->oo (mg'hIL) where 0.8 re8ects the 80 percent theophylline constituent of aminophylline.
Statistbll Analysis
Paired t test and the linear regression analysis were used as appropriate. The p values of less than 0.05 were considered signi6cant. The Bonferroni correction was used for multiple comparisons. Data are expressed as means ± SE. 10
.
& -..
eft
af
~ -'
.1
= >.
9 8 7 6 5 4
~
•l-
~
t-
•...
.,.•
3
Control Orat atbuterot
0---
