Selective effects of somatostatin analogs on human drug-metabolizing enzymes

Pharmacologic or surgical manipulation with growth hormone secretion or with the physiologic release of somatostatin and growth hormone-releasing hormone affects some rat liver enzymes, especially the sex- differentiated ones. We investigated the effects of two somatostatin analogs on several enzyme functions in six patients with carcinoid syndrome, using codeine as a probe drug. Codeine was given intravenously and its N- and Odemethylation, as well as 6glucuronidation catalyzed by CYP3A, CYP2D6, and uridine diphosphat~glucuronosyltransferase, respectively, were studied before and during treatment with somato- statins. After 3 days of treatment with somatostatins the partial metabolic clearance of codeine by N-demethylation decreased by 21% to 64% in all patients (mean change, 44%; p < 0.05), and the clearance by Odemethylation was decreased by 20% to 69% in five of the patients (mean change in all patients, 35%; p < 0.05). In contrast, the partial clearance by 6glucuronidation and the total systemic clearance of codeine were unchanged. Our results may be caused by the inhibition of growth hormone secretion induced by the somatostatins, inasmuch as direct metabolic interactions with these peptide drugs are improbable. The decline in CYP3A4 and CYP2D6 activity might have clinical implications when substrates of these enzymes with low therapeutic indices are combined with somatostatin analogs. Because the formation of morphine from codeine was altered, the analgesic effect of this drug may be reduced during concomitant treatment with somatostatins. (Clin Pharmacol Ther 1998;64:150-9.)

Eva Rasmussen, MScPharm, Barbro Eriksson, MD, PhD, Kjell Zjberg, MD, PhD, Ulf Bondesson, PhD, and Anders Rane, MD, PhD Uppsala, Sweden

The balance between the secretion of hypothalamic somatostatin and growth hormone-releasing hormone is the basis of the pulsative release of growth hormone (GH). l Somatostatin is a peptide that intermittently sup- presses GH secretion in an interplay with GH-releas- ing hormone, which stimulates both the synthesis and secretion of GH.2 Continuous administration of somatostatin or its analogs causes a suppression of GH release in humans, both in vivo3,4 and in human cell models.5 This effect is made use of in treatment of patients with acromegaly.

Pharmacologic interaction with GH secretion has been shown to perturb the hepatic CYP system in ani- mal experiments,6-9 as well as in human subjects.r@14 Therefore it was of interest to study the effects of

From the Department of Clinical Pharmacology and the Department of Medicine, University Hospital, and the National Veterinary Institute.

Supported by grants from the Swedish Medical Research Council (04496).

Received for publication Nov. 12, 1997; accepted March 4, 1998. Reprint requests: Eva Rasmussen, MScPharm, Department of Clini-

cal Pharmacology, University Hospital, S-751 85 Uppsala, Sweden. Copyright 0 1998 by Mosby, Inc. 0009-9236/98/$5.00 + 0 13/l/90053

somatostatins on different metabolic pathways cat- alyzed by drug-metabolizing enzymes.

Somatostatin analogs are also used in the treatment of patients with carcinoid syndrome to suppress tumoral release of hormones that mediate the major clinical symptoms.15,16 We used this clinical model to study the influence of somatostatins on three different metabolic pathways of codeine, two of which include demethyla- tions catalyzed by cytochromes P4502D6 (CYP2D6) and 3A (CYP3A) that lead to formation of morphine and norcodeine, respectively. 17-20 The third pathway studied was glucuronidation of codeine catalyzed by uri- dine diphosphate-glucuronosyltransferase, which leads to formation of codeine-6-glucuronide (Fig. 1).

Codeine was chosen as the probe drug because it is an innocuous drug and permits the simultaneous in vivo assessment of the three enzymatic pathways, thereby excluding any effect of experimental or physiologic variation on the comparison of clearance along these pathways. A single intravenous dose of codeine was given on day 1 before the start of treatment to assess the baseline clearance of codeine by N- and O-demethy- lation and glucuronidation. The test was repeated on day 4 after the start of therapy. A consistent decrease

150

CLlNICALPHARMACOLOC;Y&'I‘HER~PEUTICS VOIUME 64,NUMREKZ Rusmzmen et nl. 151

CH,O

_+ Codeine-6-glucuronide

Norcodeine-glucuronide

H Normorphine

Fig. 1. The metabolism of codeine.

in the partial metabolic clearance by N-demethylation was observed in all patients and a decrease in codeine clearance by O-demethylation was observed in all male patients in contrast to glucuronidation, which was unaf- fected by the treatment.

PATIENTS AND METHODS Patients. Six male patients and one female patient

with hormone-secreting gastrointestinal tract carcinoid tumors selected for treatment with a somatostatin ana- log were included in the study after each gave informed consent. The mean (&SD) age and body weight of the patients were 55 + 12 years and 70 + 15 kg, respec- tively. Patients with a history of biliary tract problems or clinically significant liver or kidney dysfunction were excluded. Some clinical features of the patients are presented in Table I. One male patient with midgut carcinoma was included in the study but was withdrawn after the first codeine dose because of itching and red- ness at the injection site. Food intake and physical activity were standardized, and concomitant medica- tion was held constant during the study. The study was approved by the ethics committee of Uppsala Univer- sity (Uppsala, Sweden).

Drug administration and sampling. Codeine was administered before and 3 days after the start of treat- ment with lanreotide (Ipsen Biotech) or octreotide (San- dostatin, Sandoz Pharma) 750 pg subcutaneously three times a day. The patients fasted for at least 10 hours before the codeine dose. Codeine, 15 mg (Apoteksbo- laget Production Unit, Umei, Sweden), was adminis- tered intravenously over 2 minutes. Blood samples were

collected before and 3, 5, 10, 30, 60, and 90 minutes and 2, 3, 4, 6, 8, 12, and 24 hours after administration of the dose. In addition, blood samples were collected for determination of insulin-like growth factor I (IGF-I) and CYP2D6 genotype. All blood samples were taken from an indwelling intravenous catheter. Urine was col- lected 0 to 12 and 12 to 24 hours after dose administra- tion. Urine and serum samples were stored at -70” C until analysis.

Analyses. Serum and urine were analyzed for codeine by gas chromatography-mass spectrometry according to the method of Quiding et a1.21 In addition, urine was analyzed after acid hydrolysis of conjugates. The interday and intraday coefficients of variation (CV) of the serum analyses were less than 4.0% at all con- centrations except for the lowest concentration (3.7 nmol/L) at which the CV was 9.6%. The interday and intraday CV values of the urine analyses were less than 6%. The limits of quantification of codeine in serum and urine were 1.0 to 2.7 nmol/L and 3.3 nmol/L, respectively. Two linear standard curves, limit of quan- tification to 414 nmol/L and 414 to 3341 nmol/L, were generated to cover the serum concentration range achieved in the patients. The ranges of urine concen- trations in the standard curves were 3.3 to 431 nmol/L and 431 to 17,900 nmol/L. The recovery of the hydrol- ysis of codeine-6-glucuronide was 8 1% to 91%.

Urine was analyzed for norcodeine by HPLC with ultraviolet detection before and after acid hydrolysis of conjugates, according to the method of Rane et a1.22 and slightly modified as follows: 2 mol/L sulfuric acid was used for hydrolysis (SO’ C for 16 hours). The

152 Rasmussen et al. CLINICAL PHARMACOLOGY & THERAPEUTICS

AUGUST 1998

Table I. Clinical features of patients

Patient Age Body weight No. Sex M-J (kg) Diagnosis and concurrent diseases Drug treatment

1 Male 76 75 Midgut carcinoid syndrome with liver metastases, angina pectoris, diabetes mellitus

2 Male 39 63 Midgut carcinoid syndrome with liver and lymph node metastases, cholecystectomy, ileoectomy

3 Male 52 90 Midgut carcinoid syndrome with liver metastasesand heart involvement, asthma

Female 54 49 Foregut carcinoid syndrome with liver and breast metastases, cholecystectomy

Male 52 60.5 Foregut carcinoid syndrome with liver metastases, benign paroxysmal dizziness

Male 60 82 Midgut carcinoid syndrome

Lanreotide, 750 ug t.i.d.; glyburide (INN,glibenclamide), 1.75 mg q.d.; nitroglycerine, 0.25 mg pm Lanreotide, 750 ug t.i.d.

Lanreotide, 750 pg t.i.d.; tryptophan, 2 gm t.i.d.; metoprolol, 100 mg q.d.; nifedipine, 20 mg b.i.d.; omeprazole, 20 mg b.i.d.; ipratropium bromide, 40 ug t.i.d.; budesonide, 400 pg b.i.d.; o-interferon, 5 million IU 5 daysiwk Octreotide, 750 pg t.i.d.; pancreatin, 300 mg t.i.d. Lanreotide, 750 ug t.i.d.; certirizin, 10 mg q.d. Lanreotide, 750 ug t.i.d.

Table II. Pharmacokinetics of codeine before and dur- ing treatment with somatostatins

Codeine Codeine plus somatostatins

CL (L/lx) 40.0 + 21 .o 38.7 + 17.7 CL, ww 4.41 + 4.1 4.30 f 2.2 vp (L) 225 f 43 225 f 94 tg (hr) 4.9 -c 2.9 5.6 f 2.8 MRT (hr) 5.1 f 1.8 4.6 + 2.6

Data are mean values f SD. CL, Clearance; CL,, renal clearance of codeine; VP. volume of distribution;

t%, half-life; MRT, mean residence time.

samples were purified by solid-phase extraction and liquid-liquid extraction before analysis. The first 0.8 ml of the eluate in the solid-phase extraction was dis- carded. The limit of quantification of norcodeine in urine was 17.5 nmol/L. The recovery of the purifica- tion process was 50% to 60%. The CV values of the analysis with and without acid hydrolysis were less than 13.8% and 17.7%, respectively. The concentra- tion range used for the standard curve was 17.5 to 1750 nmol/L.

Urine was also analyzed with respect to morphine, normorphine, morphine-3-glucuronide, and morphine-6- glucuronide by HPLC with electrochemical/ultraviolet detection according to the method of Svensson et al.23 The samples were purified by solid-phase extraction as described by Rane et al.,22 discarding the first 0.8 ml

of the eluate before HPLC analysis. The limits of quan- tification of morphine, normorphine, morphine-3- glucuronide, and morphine-6-glucuronide were 5,5, 100, and 50 nmol/L, respectively, and the standard curves cov- ered ranges up to 500, 500, 4000, and 2000 nmol/L, respectively. The interday and intraday CV values of the analyses were less than 17%.

The CYP2D6 genotype was detected in whole blood by deoxyribonucleic acid extraction, polymerase chain reaction followed by cleavage with restriction enzymes, and polyacrylamide electrophoresis according to the method of Wadelius et a1.z4 Serum from the first five patients was analyzed for IGF-I, after acid-ethanol extraction of 100 l.tl serum, with the use of a double anti- body radioimmunoassay (IGF-I by extraction kit, Nichols Institute of Diagnostics, San Juan, Calif.) on the basis of the competition between t251-labeled IGF-I and sample IGF-I. The immunocomplex was precipitated with goat anti-rabbit immunoglobulin G antibodies. The results were expressed in micrograms per liter with use of a reference standard, the First International Refer- ence Preparation of IGF-I (87/518). The minimal quan- tification limit was 30 ug/L. The within- and between- assay CV values were 6% and 8%, respectively.

The serum samples of the sixth patient were analyzed for IGF-I by a noncompetitive sandwich radioim- munoassay (IGF-I IRMA kit, Nichols Institute Diag- nostics). Two polyclonal goat antisera against human IGF-I were used, one against the amino acids 62 to 70

(:LINICAL PHARMACOLOGY 8: THERAPEUTICS VOLUME 64, NL’MREK 2 Rasmussen et al. 15 3

Codeine N-demethylation

$ 6

A

A” Patient 1 I Patient 2 Patient 3 Patient 4

Codeine 0-demethylation

3.5

3 h---l

r 2.5 4

2

1.5

1

0.5

B0 ii

Patient 1 Patient 2

Patient 5 I Patient 6

1

Patient 3 Patient 4 Patient 5 Patient 6

Fig. 2. A, Fractional clearance of codeine by codeine N-demethylation (mean difference, 3.07; 95% confidence interval [CI], 0.28 to 5.86). B, Fractional clearance of codeine by codeine 0demethylation (mean difference, 1.04; 95% CI, 0.33 to I .75).

and labeled with biotin and one against the amino acids 1 to 23 and 42 to 61 labeled with t251. The biotin- labeled sandwich complex was bound to avidin-coated beads. Aliquots of 20 pl of the patient samples were acidified to separate the IGF-I from the IGF-I binding proteins. IGF-II was added in excess to block the bind- ing proteins from recombining with IGF-I. The results were expressed in micrograms per liter with use of a

reference standard (87/5 18). The minimal detection limit was 13 pg/L. The within- and between-assay CV values were 6% and 8%, respectively.

Pharmacokinetic analysis. Pharmacokinetic analysis was done by the noncompartmental approach. Basal pharmacokinetic parameters including area under the curve [AUC(O-t), AUC(O-m)], clearance [CL; dose/ AUC(O-w)], half-life (t%; ln2/k), volume of distribution

154 Rasmussen et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

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Codeine 6-glucuronidation

10

no ~ b Patient 1

80 -

70 -

60-

50 -

3 40-

30 -

20 -

10 -

D”’ I-

Patient 1

Patient 2 Patient 3 Patient 4

Total systemic clearance of codeine

Patient 5

Patient 2 Patient 3 Patient 4 Patient 5 Patient 6

1 Patient 6

Fig. 2. C, Codeine-6-glucuronidation (mean difference, 1.40; 95% CI, -8.53 to 11.33). D, Total systemic clearance of codeine (mean difference, 1.36; 95% CI, -8.01 to 10.78). Open bars, Before somatostatin treatment; solid bars, during somatostatin treatment.

(tl/ . CL/ln2), and mean residence time (area under the first moment curve/area under the curve) were calculated with the help of the SIPHAR/WIN computer program (SIMED SA, Crete& France). Fractional formation clear- ante (CLf) was chosen as primary parameter because it

is not affected by other elimination processes and was calculated for each of the primary pathways as follows:

CLf, = (ZAe24hrmorphine + Ae,,,MsG + Ae,,M6c)/AUC(O-,)coine

CLINICAL PHAKA4ACOLOGY 8: THEW,PEUTI(:S VOLUME 64, NUMBEK 2 Rasmussen et al. 15 5

CLf, =

(CAe24hrnorcodeine + Aezdhr norcodeIne-glucuronide)/AUC(O_,)codelne

CLf, = Ae23hrCbG/AUC(O-,)codeine

in which 0 is 0-demethylation, N is N-demethylation, G is glucuromdation, AeIbhr is the molar amount of metabolite excreted in urine 0 to 24 hours after dose administration, AUC(O-00) is the area under the serum concentration-time curve, C6G is codeine-6- glucuronide, M3G is morphine-3-glucuronide, and M6G is morphine-6-glucuronide.

In addition to CLf, metabolite to drug ratios in urine (MR), the fraction of the total clearance accounted for by each pathway (fm), and renal clearance of codeine (CL,) were calculated as follows:

MR, =

(ZAe24hrmorphine + Ae13hrM3G + Ae,,,,rM6G)/Ae,4h codeine r

MR, = Ae24hrC6C/Ae24h~deine

fm, = CLfolCL

fm, = CLf$L

fm, = CLf&L

CL, = Ae23hrcOdelne/AUC(0-00)‘0deine

Statistical analysis. Paired t tests were used for sta- tistical analysis done by the StatView computer pro- gram (SAS Institute, Cary, N.C.).

RESULTS The first dose of codeine was given before the start of

treatment with the somatostatin analog, and dosing was repeated on day 4 of treatment. Except for the patient who was excluded from the study because of an injec- tion-site reaction, the patients tolerated the codeine well and adverse reactions were observed in only one patient (mild sedation). All patients were of the extensive metab- olizer CYP2D6 genotype. Patient 5 was heterozygous for the CYP2D6 wild-type allele (CYP2D6* 1) and the other patients were homozygous for this allele. The IGF-I serum concentration did not change during the treatment (122.4 + 42.5 versus 122.8 ? 51.9 pg/L). Codeine was detected for 12 to 24 hours in serum and the total recoveries of the dose in urine as drug and metabolites were 97% _t 22% and 90% +- 16% before

and during treatment, respectively. There were no statis- tically significant differences in the basal pharmacoki- netic parameters of codeine before and during treatment with somatostatin analog (Table II).

Codeine clearance by N-demethylation (CLfN) decreased by 44% 0, < 0.05; range, 21% to 64%) dur- ing treatment with somatostatins in all patients (Fig. 2, A; Table Ill). The N-demethylation metabolic ratio (MR,) decreased by 32% to 62% in five of the six patients, but this did not reach statistical significance (p = 0.074; Table III).

The clearance by 0demethylation (CLf,) was decreased by 35% (p < 0.05) during treatment with somatostatins. Individually, the O-demethylation clear- ance was decreased by 20% to 69% in all male patients (Fig. 2, B; Table III), whereas no change (-2%) was observed in the female patient. The 0-demethylation metabolic ratio (MR,) was decreased by 44% (p < 0.05: range, 16% to 58%) during treatment with the somato- statins (Table III).

The fractions metabolized by N- and O-demethyla- tion (fmN and fmo) were studied in all patients and were calculated as the ratios of the formation clearance divided by the systemic clearance of codeine in the same subject. The fraction of the clearance by O- demethylation was decreased by 32% (0.07 k 0.04 ver- sus 0.09 * 0.05, p < 0.01) during treatment with somatostatins whereas the decrease in fraction by N- demethylation did not reach statistical significance (0.10 2 0.04 versus 0.16 + 0.09, p = 0.073), although this parameter decreased in all patients.

Clearances of codeine by glucuronidation and the glucuronidation metabolic ratio (MRG) were not con- sistently changed during treatment with somatostatin analog (-61% to +79%, and -36% to +50%, respec- tively; Fig. 2, C; Table Ill). Similarly, there was no sta- tistically significant change in overall clearance of codeine. The individual changes varied from -2 1% to +26% of the clearance observed before the start of somatostatin analog treatment (Fig. 2, D).

DISCUSSION The importance of the hypothalamus-pituitary-liver

axis for hepatic drug metabolism has been subject to increasing research interest. Much of this interest stems from experimental work in rats that shows the strong influence of the GH secretion pattern on the pattern of CYP catalyzed metabolism.25%26 However, very little is known about the hypothalamus-pituitary influence on drug metabolism in human. In this study we have shown a marked and selective effect of somatostatins on two CYP-catalyzed oxidation reactions with codeine

156 Rasmussen et al. CLINICAL I’ HARMACOLOGY &THERAPEUTICS

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Table III. Fractional formation clearance and metabolite/drug ratio in urine of the three pathways before and during treatment with somatostatin analogs

Patient No.

CLfhr (uhr) CLfO (uhr)

Before During Before During

CLfG (mr)

Before During

M% tmrl

Before During

1 1.55 0.99 3.44 2.47 14.33 14.56 0.93 0.34 2 7.66 5.84 4.51 3.59 17.27 25.87 2.91 1.98 3 10.92 3.97 3.77 1.76 26.38 25.07 2.50 0.95 4 1.24 0.98 2.04 1.99 8.02 10.69 1.10 0.53 5 11.09 6.03 2.24 0.70 53.75 34.36 0.92 1.41 6 9.79 6.0 1.87 1.12 32.98 33.79 3.38 0.79 Mean + SD 7.04 + 4.54 3.97 f 2.44* 2.98 + 1.08 1.94 f 1.02* 25.5 r 16.4 24.1 LII 9.7 1.96 + 1.10 1.00 + 0.60

CLf, Fractional formation clearance; MR. metabolite/drug ratio in mine; N, N-demethylation; 0, O-demethylation; G, glucuronidation; &fore, before treatment; during, during treatment.

*p < 0.05.

as drug substrate. No effect on the glucuronidation of the drug was observed.

The two major oxidation pathways for codeine include N- and 0-demethylation, which account for approximately 15% and lo%, respectively, of the total systemic clearance in extensive metabolizers of debriso- quin (INN, debrisoquine)/dextromethorphan (CYP2D6). Both of these reactions were down-regulated after 3 days of treatment with the somatostatins. To our knowl- edge, no studies of somatostatin effects on drug metab- olism in rats or humans have been published. However, Kvistborg et al.27 observed an increased oral bioavail- ability of bromocriptine after 12 days of octreotide treatment. This was suggested to be caused by an increase in absorption or a decrease in first-pass metab- olism, supposed to be partly catalyzed by CYP3A4.28

We propose that the observed effects of somatostatins on codeine N- and 0-demethylation are mediated through a suppression of pituitary GH secretion. Our results are consistent with the increase in the CYP3A4-catalyzed erythromycin N-demethylation observed by Watkins et all4 and P.B. Watkins (personal communication, Octo- ber 1997) after GH-releasing hormone multiple-dose treatment in healthy volunteers. Our results are also in agreement with those of Cheung et al.‘3 on antipyrine (INN, phenazone) pharmacokinetics. They showed that 3 months of GH supplementation in GH-deficient adult patients increased the clearance of antipyrine from 0.33 mYmin per kilogram to 0.50 ml/mm per kilogram. It is reasonable to believe that GH suppression, as effected in our patients, would have an opposite effect on antipyrine and erythromycin although this remains to be proved. Levitsky et a1.t2 observed a decrease in caffeine N- demethylation after 1 month of replacement therapy in

six GH-deficient children, as assessed with the caffeine t3C0, breath test. However, Redmond et al.11 found opposite effects on theophylline elimination, although they measured the half-life, which was shortened from 7.5 f 4.4 hours to 3.4 + 1.2 hours during GH replacement therapy in four children. These investigators had previ- ously shown that in contrast to the effects of GH on theo- phylline, GH replacement therapy reduced the clearance and prolonged the half-life of amobarbital.10 Taken together, these reports seem to indicate an enzyme- specific regulation by GH in humans. CYP3A4 and CYPlA2 may be under opposite GH regulation. The N-demethylation of codeine shown to be decreased in our patients is catalyzed by CYP3A.1*,20 This enzyme also catalyzes erythromycin N-demethylation29 whereas CYP 1 A2 is the major enzyme involved in the N-demethy- lation of caffeine.30 CYPlA2 is also mainly responsible for the total clearance of theophylline.31-34 Antipyrine appears to be metabolized mainly by CYP3A, CYPlA2, and CYP2C in humans,35-3s and the effect of GH on the clearance of this drug is therefore difficult to interpret.

Results from clinical studies are only partly consis- tent with results obtained in rats. A comparison with rats is complicated not only by the sex-specific metabolism in this species25339 but also by differences in types of CYP enzymes that are involved in a given metabolic pathway. Previous studies in our laboratory have shown that GH treatment of rats leads to a conspicuous down- regulation of N-demethylation of morphine,6 ethyl- morphine,8 and codeine. 8~9 However, these reactions are predominantly catalyzed by the male-specific CYP2Cll as shown by experiments with CYP2Cll- specific inhibitory antibodies* and studies at the level of messenger ribonucleic acid.39

CLINICAL PHARMACOLOGY 8; THFRAPEUTICS \:OI.UME 64. NUMRER 2 Rasmussen et al. 157

MR, (Uhr) MR, (Lfhr)

Before During Before During

2.06 0.86 8.59 5.07 1.71 1.22 6.56 8.78 0.86 0.42 6.03 5.98 1.81 1.08 7.13 5.83 0.19 0.16 4.48 8.01 0.64 0.15 11.38 4.45

1.21 k 0.75 0.65 + 0.47* 7.36 r 2.39 6.35 +- 1.69

Somatostatin and its analogs are known to reduce hepatic blood flow.40341 It is conceivable that such an effect may influence the systemic clearance of moderate- to high-extraction drugs such as codeine when given intravenously.42 The lack of decrease in glucuronidation and in total clearance of codeine could be explained by a short duration of the decrease in hepatic blood flow caused by the fast elimination of the analogs (t% = 1.5 and 2.7 hours for lanreotide and octreotide, respectively).43.44 It is unlikely that our results have been influenced by a reduction in hepatic blood flow inasmuch as no decrease in the major metabolic elimination pathway through codeine glucuronidation was observed. A metabolic inter- action between the somatostatin peptides and codeine is also highly unlikely. It is not probable that somatostatin peptides are metabolized by CYP enzymes. Other effects of somatostatins include inhibition of glucagon and insulin release, inhibitory actions on the neuropeptide release from the gut and pancreas, and inhibition of the stimulatory effects of thyroid-releasing hormone on release of thyroid-stimulating hormone.45 They also inhibit the luteinizing-hormone-release hormone stimu- lation of luteinizing hormone release.46v47 Our study does not permit us to exclude contribution of these endocrine effects to the results observed. Somatostatin also prolongs orocecal transit time and inhibits gastrointestinal tract secretion and contraction of the biliary tract, including the gallbladder.46348 However, none of these effects is likely to interfere in our clinical model.

Initial data on codeine kinetics in our patients showed that their disposition of the drug was normal. The values of clearance, terminal half-life, and volume of distribution were similar to those reported in the lit- erature.@,j’J Thus it is reasonable to assume that the

liver metastases were not influencing the overall hepatic metabolic disposition of codeine.

It is theoretically possible that our results may have clinical implications when treatment with somatostatin or its analogs is combined with drugs oxidized by CYP3A4 or CYP2D6, particularly if the therapeutic index of the drug is low. Because morphine has been proposed to be at least partly responsible for the phar- macologic effects of codeine,51 it is possible that the analgesic effect obtained after codeine administration could be reduced during concomitant somatostatin ana- log treatment. Clinical restraints in this study precluded the possibility of investigating the long-term effects of somatostatins. Such studies are also difficult to perform because of such factors as disease progression and the continuous interference by other drugs. However, fur- ther clinical studies on long-term treatment with somatostatin analogs are warranted.

We acknowledge the excellent technical assistance of Mrs. Bir- gitta Ask and Mrs. Elisabeth Fredriksson. We also acknowledge the excellent assistance of the skilled staff of the endocrinology ward.

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