Eur J Clin Pharmacol (1991) 41:449-452

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Pharmacokinetics of caffeine in patients with decompensated Type I and Type II diabetes mellitus T. Zysset l and H. Wietholtz 2 i Department of Pharmacy, Regionalspital Biel, Biet, Switzerland 2 Department of Internal Medicine, Neues Klinikum, Aachen, FRG Received: November 5, 1990/Accepted in revised form: April 16, 1991

Summary. Diabetes m a y alter the pharmacokinetics of

Materials and methods

a m i n o p y r i n e and antipyrine, which are used to assess liver function. Caffeine has recently b e e n used to test liver function, but the effect of diabetes on caffeine kinetics is not known. T h e kinetics of caffeine has b e e n e x a m i n e d in patients with d e c o m p e n s a t e d T y p e I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the a p p a r e n t caffeine clearance, halflife, and a p p a r e n t v o l u m e of distribution were similar to controls. It is concluded that d e c o m p e n s a t e d diabetes does not influence the c y t o c h r o m e P-448 m o n o - o x y g e n a s e system responsible for caffeine metabolism.

Subjects

Key words: D i a b e t e s mellitus, Caffeine; p h a r m a c o k i n e tics, P-450 m o n o - o x y g e n a s e

Diabetes can alter the p h a r m a c o k i n e t i c s of a n u m b e r of drugs in animals and m a n [1-6]. T h e changes are assumed to be due to qualitative and quantitative differences in the composition of the c y t o c h r o m e P-450 m o n o - o x y d a s e system [7], as well as to altered drug distribution [5]. A m o n g s t the drugs whose m e t a b o l i s m is altered by diabetes, a m i n o p y r i n e and antipyrine are extensively used for testing liver function [8-14]. Thus, diabetes m a y affect the reliability of such tests. Caffeine has recently b e e n used to quantify liver function [15-17]. Caffeine and antipyrine are metabolized by different isoforms of the m o n o - o x y g e n a s e system, caffeine by a 3-methylcholanthrene-inducible isoenzyme [18], and antipyrine by a p h e n o b a r b i t o n e - i n d u c i b l e cyt o c h r o m e P-450 [19]. H o w e v e r , it is not k n o w n w h e t h e r diabetes alters the c y t o c h r o m e P-448 or polycyclic aromatic arylhydrocarbon-inducible isoenzyme responsible for caffeine metabolism. To answer this question, caffeine m e t a b o l i s m has b e e n e x a m i n e d in patients with d e c o m p e n s a t e d Type I and Type II diabetes and controis.

19 diabetic in-patients were studied, who were hospitalized because of deterioration of their diabetes. Ten were classified as having Type I and nine as having Type II diabetes. The Type I patients had the juvenile-onset type of diabetes; they were insulin-dependent, and they had C-peptide concentrations below 400 pmol.1-~. Their mean age was 33.3 (13.6) y and the mean duration of their illness was 12.6 (10.5) y. The Type II patients were classified according to the serum Cpeptide concentration [1030 (1590)pmol.l-1]. Six type II diabetes were taking insulin and three were on oral hypoglycaemic drugs. Their mean age was 64.8 (6.7) y, and the mean duration of the illness in them was 14.6 (11.1) y. The diabetics did not have liver damage, as assessed by routine laboratory tests, including serum albumin, transaminases, y-glutamyl transpeptidase, alkaline phosphatase, bilirubin, prothrombin time, and ultrasonography of the liver. Renal function, assessed by serum creatinine concentration and blood urea nitrogen (BUN), was normal. Both sets of diabetics were compared with healthy, sex-matched controls of a similar age range (hospital staff and their families). All the controls had normal clinical findings and routine laboratory tests. Abdominal ultrasonography was normal. One Type I diabetic and six of the Type II diabetics took oral medication, mostly cardioactive or antirheumatic drugs. In every group there were some smokers. Details of the patients and their controls are given in Table 1.

Protocol The subjects abstained from caffeine for 24 h before the study and fasted overnight. A blood sample was taken for clinical chemistry tests measurement and of the basal caffeine concentration. At 0800 h caffeine was taken as instant coffee containing 280 mg caffeine and 4 g decaffeinated coffee powder (kindly provided by Haco SA, G~imlingen, Switzerland). No other methylxanthines were allowed during the study. Blood samples were collected into heparinized tubes 0.25, 0.5, 0.75, 1, 3, 5, 7, 9, and 12 h after the caffeine. Plasma was separated by centrifugation and was stored at -20°C until analysed within 3 months.

Assays Biochemical measurements were made by standard procedures. Plasma C-peptide concentrations were measured using a commer-

450

T. Zysset and H. Wiethottz: Caffeine kinetics and diabetes

Table 1. Clinical and laboratory details of diabetics and controls. Mean with SD and range Group

n Age(y) (Women)

Reference Controls forType I 8 (3) diabetics Type I diabetics 10 (6)

Controls forTypeII 9(7) diabetics Type II diabetics

9 (6)

24.0 (4.2) (16-30)

Bodyweight Smokers Concomitant (kg) drug treatment (Number of patients in parentheses)

Duration Insulin Oralhypoof (n) glycaemics diabetes (n) (y)

Fasting blood glucose (mmol. 1- ') 3.8-6.2

Fasting C-peptide (pmol. I- 1) 370-1200

1 (1) 2 (1) 3 (1)

12.6 (10.5) 10 (0.545)

-

14 (5) (3.5-21.6)

133 (133) (33-400)

2 (3) 4 (2) 5 (1) 6(1) 7(1) 8(1) 9(1) 10(1) 11 (i) 12(i)

14.6 (11.1) 6 (1-30)

3

11 (4) (5.5-19.9)

1030 (1590) (33-4850)

70.4(9.7) (60-86)

33.3 (13.6) 68.4 (14.4) (22-56) (45-87)

56.7(8.6) (47-75)

67.7(10.7) (55-84)

64.8 (6.7) (52-74)

64.2(8.2) (52-80)

3

Drug treatments: 1) Amoxicillin 2) Nifedipine 3) Sotalol 4) Digoxin 5) Frusemide 6) Isosorbide dinitrate 7) Norfenephrine 8) Molsidomine 9) Quinidine sulphate 10) Theophylline 11) Phenprocoumon 12) Pirenzepine

Table 2. Pharmacokinetics of caffeine in Type I and II diabetics and their controls. Mean with SD Half-life

Cmax

Volume of distribution (ml.kg < ) (1)

Clearance (ml.min-l-kg -1)

(ml. min -1)

(btm°l 1 ~)

tmax (rain)

Controls Type I Diabetics Type I P vs controls

4.9 (1.1) 4.4 (1.8) NS

595 (61) 619 (112) NS

42.0 (8.5) 41.8 (9.4) NS

1.3 (0.4) 1.7 (0.6) NS

92.6 (26.2) 114.5 (45.7) NS

31.6 (5.7) 38.0 (6.8) NS

89 (41) 35 (31) < 0.01

Controls Type II Diabetics Type If P vs controls

4.2 (1.6) 5.6 (3.4) NS

505 (94) 547 (134) NS

33.9 (6.9) 35.1 (9.2) NS

1.5 (0.7) 1.4 (0.8) NS

96.3 (33.2) 88.7 (43.8) NS

44.0 (7.2) 41.1 (9.0) NS

16 (18) 42 (30) < 0.05

cial RIA kit (C-Pep-Da-Peg-Ria-100, IRE, FIeurus, Belgium) [20]. Caffeine was measured by an automated enzyme immunoassay (EMIT, Syva, Palo Alto, CA, USA) [21].

peak caffeine concentration, the basal level was subtracted from Cmax.

All values are expressed as mean (SD). Group means have been compared by analysis of variance followed by Student's t-test [23].

Calculations

Results The pharmacokinetics of caffeine in plasma was calculated using the R-strip fitting program (Micromath Scientific Software, Salt Lake City, USA). In all cases, two exponentials were fitted to the data: C (t) = G (e -~zt- e-k~t)

AUC extrapolated to infinity was calculated by integration. Apparent clearance was calculated as dose/AUC, assuming complete absorption of caffeine [22]. The apparent volume of distribution (V) was calculated as V = Dose.AUMC/(AUC) 2. The time to reach the peak caffeine concentration (tmax)and the peak caffeine concentration (Cmax)were calculated by the R-strip program. In the few cases in whom a basal caffeine concentration was detected at time 0, the AUC of this concentration was calculated as C(0)/)vz and it was subtracted from the total AUC. To calculate the

T h e two groups of patients did not differ in their routine laboratory tests, with the exception of the C-peptide concentration, which clearly distinguished the Type I and Type II diabetics (Table 1), in a g r e e m e n t with other studies [6, 24]. Caffeine clearance in all the groups was within the expected range for subjects with n o r m a l liver function [15, 16, 25-28]. The a p p a r e n t v o l u m e of distribution, a p p a r e n t clearance, half-life, and p e a k concentrations of caffeine did not differ b e t w e e n diabetic patients and their controls. In contrast, the time to p e a k c o n c e n t r a t i o n differed significantly b e t w e e n diabetics and controls. In Type I diabetics the time to p e a k was 2.5-times slower than in the controls, and in Type II patients it was 2.6-times faster.

451

T. Zysset and H. Wietholtz: Caffeine kinetics and diabetes

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The study showed that caffeine differs in various aspects f r o m other substrates used to assess liver function. The pharmacokinetics of aminopyrine in animals and of antipyrine in animals and patients were significantly altered in diabetes [2-6, 32], whereas caffeine kinetics were not changed. The reason for the diabetes-associated differences between the kinetics of caffeine and antipyrine is not clear. However, it appears that the disposition of antipyrine is related to overall cytochrome P450 activity, whereas caffeine metabolism appears primarily to depend on the polycyclic aromatic arylhydrocarbon-inducible isoenzyme responsible for caffeine metabolism [33]. The results suggest that diabetes does not significantly alter this cytochrome P448 mono-oxygenase system. The present findings are in keeping, therefore, with the well known heterogeneity of the mono-oxygenase system, which comprises multiple forms of cytochromes with different catalytic activities and overlapping substrate specificities [33, 34].

Acknowledgement. We are grateful to Professor Dr. R.Preisig, Head, Department of Clinical Pharmacology, University of Berne, Berne, Switzerland, for permitting us use the Cobas Bio Analyzer in his Drug Assay Unit.

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Fig. 1. a Caffeine pharmacokinetics in patients with Type I diabetes

(n:10) and their age- and sex-matched controls (n :8) e, -- Diabetes Type I ; ; Controls Type I, and b in patients with Type II diabetes (n = 9) and their controls (n = 9) -" e, Diabetes Type II ; ; Controls Type II

The peak plasma caffeine concentrations in the Type II diabetics and their controls were significantly higher than in the Type I patients and their controls. Plasma concentrations of caffeine are shown in Figs. i a, b.

Discussion

A p p a r e n t caffeine clearance, half-life, and the apparent volume of distribution were not affected by Type I and Type II diabetes. The significant prolongation of the time to peak of the plasma caffeine in Type II diabetes m a y have been due to delayed gastric emptying caused by gastroparesis, a well known complication of diabetes [29, 30]. The reason for the shorter absorption time in Type I diabetics is not clear. However, in younger diabetics without diabetic complications, accelerated gastric emptying due to hypermotilinaemia has been described [31]. Previous studies in non-diabetic subjects have shown complete absorption of caffeine [22, 25]. In these studies complete absorption was assumed, although proof of this assumption in diabetics is still lacking. It is unlikely that the medications taken by some of the subjects (mostly Type II diabetics) influenced the outcome of the results, since the drugs involved are not known to influence the metabolism of other drugs.

References

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T. Zysset Ph.D. Regionalspital Biel Spitalapotheke CH-2502 Biel Switzerland