Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses

Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses

European Journal of Pharmaceutical Sciences 18 (2003) 121–128 www.elsevier.com / locate / ejps Pharmacokinetics and bioavailability of denaverine hyd...

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European Journal of Pharmaceutical Sciences 18 (2003) 121–128 www.elsevier.com / locate / ejps

Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses ´ Alexander Staab a , *, Barbara S. Schug a ,1 , Veronique Larsimont a ,2 , Martina Elze a ,3 , b c ¨ Daniela Thummler , Ernst Mutschler , Henning Blume a ,1 a

Zentrallaboratorium Deutscher Apotheker, Carl-Mannich-Str. 20, 65760 Eschborn, Germany b ¨ . 27, 01309 Dresden, Germany Apogepha Arzneimittel GmbH, Kyffhauserstr c ¨ Naturwissenschaftler, J.W. Goethe-Universitat ¨ , Biozentrum Niederursel, Marie-Curie-Str. 9, Pharmakologisches Institut f ur 60439 Frankfurt, Germany Received 15 February 2002; received in revised form 17 October 2002; accepted 28 October 2002

Abstract The neurotropic-musculotropic spasmolytic agent denaverine hydrochloride is used mainly in the treatment of smooth muscle spasms of the gastrointestinal and urogenital tract. Despite its commercial availability as a solution for intravenous or intramuscular administration (ampoule) and as a suppository formulation, no pharmacokinetic data in man was available to date. Therefore, the objectives of this clinical trial were to determine the basic pharmacokinetic parameters of denaverine after intravenous administration, to assess the feasibility of using the oral route of administration and to characterise the bioavailability of the suppository formulation. To achieve this, healthy subjects received 50 mg denaverine hydrochloride intravenously, orally and rectally in aqueous solutions and rectally as suppository in an open, randomised crossover design. Total body clearance, volume of distribution at steady-state and half-life of denaverine are 5.7 ml / min per kg, 7.1 l / kg and 33.8 h, respectively. The absolute bioavailability after oral administration of an aqueous solution is 37%. First-pass metabolism leading to the formation of N-monodemethyl denaverine was found to be one reason for the incomplete bioavailability after oral administration. Rectal administration of an aqueous solution of denaverine hydrochloride resulted in a decreased rate (median of Cmax ratios: 26%, difference in median t max values: 1.9 h) and extent (31%) of bioavailability compared to oral administration. Using the suppository formulation led to a further reduction in rate (median of Cmax ratios: 30%, difference in median t max values: 3 h) and extent (42%) of bioavailability compared to the rectal solution.  2002 Elsevier Science B.V. All rights reserved. Keywords: Denaverine hydrochloride; Denaverine; N-Monodemethyl denaverine; Bioavailability; Pharmacokinetics; Suppository; First-pass metabolism

1. Introduction Denaverine hydrochloride, 2-dimethylaminoethyl 2-(2-

*Corresponding author. Present address: Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. Tel.: 149-7351545294; fax: 149-7351-835294. E-mail address: [email protected] (A. Staab). 1 Present address: SocraTec R&D Ltd., Feldbergstr. 59, 61440 Oberursel, Germany. 2 Present address: IMFORM GmbH, Birkenweg 14, 64295 Darmstadt, Germany. 3 Present address: ClinResearch GmbH, Robert-Perthel-Str. 77a, 50739 ¨ Germany. Koln,

ethylbutoxy)-2,2-diphenylacetate hydrochloride (Fig. 1) is a neurotropic-musculotropic spasmolytic agent with addi¨ ¨ tional analgesic activity (Huller et al., 1969; Huller, 1970; Scharein and Bromm, 1998). It is used in the treatment of smooth muscle spasms of the gastrointestinal and urogeni¨ tal tract (Huller, 1970), in the treatment of postoperative abdominal pain and in the field of obstetrics (Amon and ¨ Amon, 1968; Vesper, 1971; Kopernik and Schwarz, 1973; Zimmer et al., 1974; Neumayer, 1975; Zanke et al., 1978; Bredow, 1992). A recent randomised, double-blind, multicentre, parallel group trial demonstrated that denaverine hydrochloride (intravenous administration) is as effective as butylscopolamine bromide (intravenous administration) in the treatment of pain in acute renal colic (Apogepha, in preparation). Denaverine hydrochloride is available on the market as a solution for intravenous or intramuscular

0928-0987 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0928-0987( 02 )00225-7

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2. Experimental procedures

2.1. Study design

Fig. 1. Structural formulae.

administration (ampoule) and as a suppository formulation. Although denaverine hydrochloride has been used successfully in therapy for more than 30 years, no information about its pharmacokinetic properties or the bioavailability of the suppository formulation has been available to date. Furthermore, no information about the biotransformation of denaverine in man was available. The objectives of the present study were to determine the basic pharmacokinetic parameters of denaverine after intravenous administration as denaverine hydrochloride and to characterise the bioavailability of the suppository dosage form. Due to the convenience of administration, an oral formulation could be a useful addition to the already marketed intravenous and rectal preparations. Therefore, a further objective of the study was to assess the feasibility of using the oral route of administration with regard to rate and extent of bioavailability. To achieve these objectives, denaverine hydrochloride was administered intravenously, orally and rectally in aqueous solutions as well as rectally using the marketed suppository formulation.

The study was carried out in accordance with the Declaration of Helsinki and its amendment of 1989 and the protocol was approved by an independent ethics committee. After giving written informed consent, nine young healthy female subjects (age: 23.962.6 years, weight 63.364.8 kg, height: 172.265.3 cm; means6S.D.) and nine young healthy male subjects (age: 26.261.6 years, weight 73.066.9 kg, height: 179.968.1 cm; means6S.D.) participated in the study. Single doses of 50 mg denaverine hydrochloride were administered under fasting conditions (12 h overnight) according to an open, randomised, crossover design with a wash-out period of 7 days. The first six subjects received denaverine hydrochloride intravenously and orally as aqueous solutions as well as rectally as suppository formulation. An administrative intermediate analysis was planned and carried out after these six subjects had been dosed in order to review different design aspects because very little was known about the pharmacokinetics of denaverine hydrochloride. As the absolute bioavailability of the suppository formulation was low, the administration of an experimental solution for rectal administration was included in the second part of the study (subjects No. 7 to 18). Subjects No. 7 to 12 received in addition to the treatments of the first part of the study the experimental solution for rectal administration. Subjects No. 13 to 18 received only the experimental solution for rectal administration and the suppository formulation. The intravenous administration of denaverine hydrochloride was not carried out for subject No. 11. This study design allowed to characterise the influence of the suppository formulation on the bioavailability of denaverine comprehensively by comparing the bioavailability data for the suppository formulation to the data obtained after rectal administration of an experimental aqueous solution of denaverine hydrochloride. The bioavailability after oral administration could be evaluated by comparing the results of the oral administration of an aqueous solution of denaverine hydrochloride to the results after intravenous administration as well as to the results after the rectal administration of an aqueous solution of denaverine hydrochloride.

2.2. Formulations and administration For intravenous and oral administration of an aqueous solution as well as rectal administration of a suppository formulation, the commercially available products ¨ Spasmalgan  -Ampullen Injektionslosung and Spasmalgan  ¨ Zapfchen (Apogepha Arzneimittel GmbH, Dresden, Germany) were used. The Spasmalgan  -Ampullen Injek-

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¨ tionslosung contained 10 mg denaverine hydrochloride in 1 ¨ ml of solution and one Spasmalgan  -Zapfchen suppository contained 50 mg of denaverine hydrochloride. The experimental solution for rectal administration (10 mg denaverine hydrochloride in 1 ml solution) was prepared by the pharmacy of the university hospital Carl Gustav Carus of the University of Technology of Dresden. Denaverine hydrochloride was dissolved in aqua ad iniectabilia and glycerol 85% (29.8 mg in 1 ml) was added to make the solution isotonic in order to avoid defecation stimuli. A dose of 50 mg of denaverine hydrochloride was administered in each treatment. The intravenous administration of denaverine hydrochloride was carried out with the help of an automatic perfusor. The entire dose of 50 mg denaverine hydrochloride (5 ml Spasmalgan  -Ampul¨ len Injektionslosung) was infused over 15 min after dilution with 20 ml isotonic saline. After the end of intravenous infusion, the subjects remained in the supine position for at least 30 min. The oral solution dose of 50 mg denaverine hydrochloride (5 ml Spasmalgan  -Ampul¨ len Injektionslosung) was taken in a sitting position using a polypropylene plastic cup which was rinsed twice with a total of 150 ml weakly carbonated mineral water. Before administration of the rectal formulations (solution, suppository), the subjects were asked to defecate if possible. For application of the 50 mg denaverine hydrochloride in the rectal solution (5 ml) a 10-ml disposable plastic syringe was used to which a plastic application tube was connected. The rectal solution was slowly administered over 1 min. After administration of the suppositories as well as the rectal solution, the subjects remained in the left lateral position for at least 30 min. Thereafter, for the rectal solution, the subjects had to stay in the left lateral or abdominal position for a further 90 min. No subject reported defecation during the first 2 h after administration of the rectal formulations.

2.3. Safety Each subject had a routine medical examination before the start and after the end of the study. All adverse events were reported in detail.

2.4. Blood sampling In the case of the intravenous infusion, blood samples were drawn prior to drug administration and 5, 10, 15, 20, 30, 40, 50 min as well as 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h after the beginning of the infusion. In the case of the oral and rectal aqueous solutions, blood samples were withdrawn prior to dosing and 10, 20, 30, 45 min, as well as 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h after administration. In the case of the suppository formulation, blood samples were withdrawn prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16,

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20 (subjects No. 1 to 6 only), 24, 36 and 48 h after dosing. The volume of blood taken per blood sample was 10 ml for subjects No. 1 to 6 and 13 to 18, whereas the blood volume per sample was reduced to 8 ml for subjects No. 7 to 12. Although large total blood volumes were taken during the study, none of the subjects reported any adverse event that could be attributed to this blood loss. Blood samples were centrifuged (20003g, 10 min, 4 8C) and plasma was transferred into polypropylene tubes. The plasma samples were stored frozen (#222 8C) until analysis.

2.5. Analytical method The determination of denaverine in plasma (subjects No. 1 to 6) was carried out using a validated isocratic reversedphase high performance liquid chromatographic method (Staab et al., 2001). Samples were spiked with the internal standard (2-diethylaminoethyl 2-(2-ethylbutoxy)-2,2diphenylacetate hydrochloride) and extracted with a n-heptane / 2-propanol mixture (9:1, v / v). This was followed by back extraction into phosphoric acid 12.5% (w / w). Aliquots were injected into the chromatographic system equipped with an ultraviolet detector set at an operational wavelength of 220 nm. The results were calculated by the internal standard method. Screening of chromatograms of plasma samples from the first six subjects for possible metabolites resulted in the detection of a metabolite of denaverine. Its structure was identified as the N-monodemethyl metabolite of denaverine (2-methylaminoethyl 2-(2-ethylbutoxy)-2,2-diphenylacetate, MD 6, Fig. 1) (Staab et al., 2001). The metabolite MD 6 was determined in subjects No. 7 to 18 as information about the pharmacokinetics of MD 6 could help to understand the pharmacokinetics and bioavailability results for the parent compound. The assay for the determination of denaverine (subjects No. 1 to 6) and for the simultaneous determination of denaverine and MD 6 (subjects No. 7 to 18) was validated according to international requirements. The lower limit of quantification for denaverine and MD 6 was 2.5 ng / ml. Accuracy of the method, expressed in terms of relative errors, lay between 24.8 and 23.0% for denaverine and 21.9 and 2.8% for MD 6 in the concentration range 2.5–150 ng / ml. Precision, given by the coefficients of variation lay between 2.8 and 5.7% for denaverine and between 3.5 and 8.1% for MD 6 in the same concentration range.

2.6. Pharmacokinetic analysis All pharmacokinetic parameters were determined by non-compartmental analysis. The maximum plasma concentration (Cmax ) and the time to reach Cmax (t max ) were taken directly from the observed concentration versus time

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profiles. The slopes of the ln-linear portion of the individual pharmacokinetic profiles for denaverine were determined by least-squares regression analysis and used as the apparent terminal elimination rate constant (Ke ). For MD 6 also the observed plasma concentrations were used to determine the apparent terminal elimination rate constant as described for denaverine. The apparent elimination half-life (t 1 / 2 ) was calculated as 0.693 /Ke . The area under the concentration versus time curve from time zero to the last quantifiable point (AUC 0 – t ) was calculated by the linear trapezoidal rule from time zero to t max and by the log-linear trapezoidal rule beyond t max until the last quantifiable plasma concentration (Ct ). Extrapolated area under the curve from the time of Ct to infinity (AUC t – inf ) was determined as Ct,fit /Ke , where Ct,fit is the fitted concentration according to regression analysis at time of Ct . Total area under the curve (AUC 0 – inf ) was the sum of AUC 0 – t and AUC t – inf . Total body plasma clearance after intravenous administration (CL) was calculated as dose / AUC 0 – inf . The volume of distribution at steady state (Vss ) was calculated according to the following equation (Gibaldi and Perrier, 1982), whereby AUMC is the area under the first moment versus time curve and time infusion is the duration of the infusion. Dosis ? AUMC Dosis ? time infusion Vss 5 ]]]] 2 ]]]]] 2 ? AUC 02inf (AUC 02inf )2

2.7. Statistical analysis Statistical analyses were carried out using logarithmically transformed data for AUC 0 – t , AUC 0 – inf , Cmax , CL and Vss while for t max and t 1 / 2 , the untransformed data were used (FDA, 2001). The geometric mean (Geo. Mean) and geometric coefficient of variation (gC.V.) were used as descriptive statistics for the logarithmically transformed data, for t max median and range are given and for t 1 / 2 arithmetic mean and standard deviation (S.D.) are given as descriptive statistics. After rectal administration of denaverine hydrochloride, the terminal half-lives could not be determined reliably for all subjects, thus, AUC 0 – t instead of AUC 0 – inf was used to describe the extent of bioavailability. Furthermore, MD 6 concentrations were too low to estimate any pharmacokinetic parameters after administration of the suppository formulation. To assess the intraindividual comparisons, point and interval estimates for the AUC 0 – t or AUC 0 – inf and Cmax ratios were calculated. For each comparison with 11 or 12 subjects, an analysis of variance of the particular individual data was carried out assuming a two-way crossover design. The factors formulation, period, sequence and the subject nested within sequence were taken into consideration. In this way, residual variabilities were estimated. The ratios of geometric means served as point estimates for these comparisons and 95% confidence intervals served as interval estimates.

Medians and ranges of individual AUC 0 – t or AUC 0 – inf and Cmax ratios were used to assess the comparisons with five or six subjects.

2.8. Data processing Pharmacokinetic and statistical analyses were carried out using the following software programs: Access (version 2.0, Microsoft Corporation, USA), Excel (version 5.0, Microsoft Corporation, USA) and SAS (version 6.11 for PC under Windows, SAS Institute Inc., Cary, NC, USA).

3. Results and discussion Figs. 2 and 3 present the mean plasma concentration versus time profiles of denaverine and MD 6 after intravenous, oral and rectal administration of aqueous solutions of denaverine hydrochloride as well as after administration of the suppository formulation. Summaries of the main pharmacokinetic parameters are shown in Tables 1 and 2. Table 3 lists the point and interval estimates for the intraindividual treatment comparisons. The blood sampling period from 0 to 48 h was adequate for the main purposes of the study namely to assess the feasibility of using the oral route of administration for denaverine and to evaluate the bioavailability of the suppository dosage form, as the main differences between the different treatments were observed during the first 16 h whereas beyond 16 h, the curves roughly decline in parallel, suggesting similar disposition kinetics. The similar apparent terminal half-lives of denaverine after intravenous and oral administration confirm this (Table 1). A description of the plasma concentration versus time pro-

Fig. 2. Semi-logarithmic plot of the mean plasma concentrations of denaverine after intravenous (n511), oral (n512), and rectal (n512) administration of denaverine hydrochloride solutions (50 mg) and rectal administration of the suppository formulation (50 mg, n518).

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be, especially for rectal administrations, the development of a new assay with a limit of quantification that is lower than 2.5 ng / ml. Regarding adverse events, denaverine hydrochloride was in general well tolerated with all routes of administration. Adverse events associated with the medication occurred only locally (n59), mainly following administration of the aqueous solutions (irritation of vascular wall and irritation of mucous membrane in the throat and in the rectum) and were mild to moderate in severity.

3.1. Pharmacokinetics of denaverine after intravenous administration as denaverine hydrochloride

Fig. 3. Plot of the mean plasma concentrations of MD 6 after intravenous (n55), oral (n56) and rectal (n512) administration of denaverine hydrochloride solutions (50 mg).

files beyond 48 h would be desirable for a complete description of the pharmacokinetics of denaverine and the metabolite MD 6. However, a prerequisite for this would

After reaching the peak concentration at the end of the infusion, the mean profile after intravenous administration of 50 mg denaverine hydrochloride declined rapidly. The terminal elimination phase starting approximately 16 h after the beginning of administration had a gentle slope (Fig. 2). CL, Vss and t 1 / 2 were determined to be 5.7 ml / min per kg (gC.V., 29%), 7.1 l / kg (gC.V., 33%) and 33.8 h (S.D., 612.1 h), respectively (Table 1). The similar terminal half-lives of parent compound and metabolite MD 6 (Tables 1 and 2) suggest that the

Table 1 Mean pharmacokinetic parameters and associated statistics for denaverine following administration of 50 mg denaverine hydrochloride as intravenous solution, oral solution, rectal solution and suppository formulation Study medication

AUC 0 – t (ng?h / ml); Geo. Mean (gC.V. (%))

AUC 0 – inf (ng?h / ml); Geo. Mean (gC.V. (%))

Cmax (ng / ml); Geo. Mean (gC.V. (%))

t max (h); Median (range)

t1 / 2 (h); Arith. Mean (S.D.)

Intravenous solution (n511) Oral solution (n512) Rectal solution (n512) Suppository (n518)

1698 (22) 546 (39) 239 (99) 121 (109)

2018 (27) 711 (38) –

1434 (47) 110 (38) 29 (43) 9.6 (40)

0.17 (0.17–0.33) 1.1 (0.5–1.5) 3.0 (3.0–6.0) 6.0 (3.0–24.0)

33.8 (12.1) 31.4 (9.8) –





Geo. Mean, geometric mean; Arith. Mean, arithmetic mean; gC.V., geometric coefficient of variation.

Table 2 Mean pharmacokinetic parameters and associated statistics for MD 6 following administration of 50 mg denaverine hydrochloride as intravenous solution, oral solution and rectal solution Study medication

AUC 0 – t (ng?h / ml); Geo. Mean (gC.V. (%))

AUC 0 – inf (ng?h / ml); Geo. Mean (gC.V. (%))

Cmax (ng / ml); Geo. Mean (gC.V. (%))

t max (h); Median (range)

t1 / 2 (h); Arith. Mean (S.D.)

Intravenous solution (n55) Oral solution (n56) Rectal solution (n512)

410 (34) 489 (31) 74 (145)

600 (55) 561 (38) –

27 (22) 37 (27) 4.2 (49)

1.0 (0.83–3.0) 3.0 (2.0–4.0) 5.5 (3.0–16.0)

32.8 (14.2) 17.1 (6.4) –

Geo. Mean, geometric mean; Arith. Mean, arithmetic mean; gC.V., coefficient of variation.

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Table 3 Statistical results of treatment comparisons for AUC and Cmax Parameter

Treatment comparison

Denaverine

MD 6

Point estimate (%)a

Interval estimate (%)b

Point estimate (%)a

Interval estimate (%)b

AUC c

Oral / intravenous Rectal / intravenous Rectal / oral Suppository / intravenous Suppository / oral Suppository / rectal

37 10 31 8 20 42

(n511) (n55) (n56) (n511) (n512) (n512)

27–51 5–24 16–61 5–13 11–36 21–85

114 (n55) 10 (n55) 7 (n56) – – –

58–168 3–46 3–23 – – –

Cmax

Oral / intravenous Rectal / intravenous Rectal / oral Suppository / oral Suppository / rectal

– – 26 (n56) 8 (n512) 30 (n512)

– – 11–44 6–11 21–43

128 (n55) 11 (n56) 8 (n56) – –

113–268 7–21 6–11 – –

a

Ratios of geometric means for comparisons with 11 or 12 subjects, median of individual ratios for comparisons with five or six subjects. Confidence intervals (95%) for comparisons with 11 or 12 subjects, ranges of individual ratios for comparisons with five or six subjects. c AUC 0 – inf for the comparison oral / intravenous, AUC 0 – t for all other comparisons. b

elimination of MD 6 was formation rate limited and that the true elimination half-life of MD 6 is shorter than the apparent one.

3.2. Evaluation of the oral route of administration for denaverine hydrochloride 3.2.1. Intravenous versus oral administration of aqueous solutions of denaverine hydrochloride The mean plasma concentration versus time curve of denaverine increased rapidly after oral administration of 50 mg denaverine hydrochloride resulting in a maximum 1 h after administration (Fig. 2). Starting 5 h after administration, the profiles of oral and intravenous administration declined in parallel. The mean plasma concentration versus time curve after intravenous administration of denaverine hydrochloride was much higher than after oral administration of the same dose. The absolute bioavailability was determined to be 37% (95% C.I., 27–51%, Table 3). In principle, there were various possible reasons that could explain the reduced absolute bioavailability of denaverine after oral administration: incomplete absorption, instability in the gastrointestinal tract (physical, chemical, enzymatic), first-pass metabolism, or any combination of these reasons. Using the data collected during the course of the current study, the aspect of first-pass metabolism of denaverine can be discussed thoroughly. During the entire period of blood sampling, the mean plasma concentration curve of MD 6 after oral administration of denaverine hydrochloride was in general higher than the mean curve after intravenous administration (Fig. 3), which was reflected in the median of the individual AUC 0 – ` ratios of 114% (range, 58–164%, Table 3). This point estimate of the metabolite for the comparison oral versus intravenous administration was higher than the point estimate of the parent compound (114 vs. 37%,

Table 3), indicating that denaverine was subjected to a first-pass effect. The rapid increase in plasma concentrations of MD 6 after oral administration supported this interpretation. The pharmacological activity of MD 6 is not known. The N-monodeethyl metabolite of oxybutynine, a substance that is structurally similar to denaverine, showed anticholinergic activity similar to that of the parent compound (Hughes et al., 1992). An investigation of the pharmacological activity of MD 6 should be undertaken to determine whether MD 6 might contribute to the clinical efficacy of denaverine hydrochloride.

3.2.2. Rectal versus oral administration of aqueous solutions of denaverine hydrochloride Over the entire blood sampling period, the mean profile of denaverine after oral administration of an aqueous solution of denaverine hydrochloride was higher than after rectal administration of an aqueous solution of denaverine hydrochloride (Fig. 2). The slower increase in the curve after rectal administration in comparison to oral administration and the resulting delayed and lower maximum were obvious. Quantification of these observations revealed that the relative bioavailability (extent) of denaverine after rectal administration compared to oral administration was reduced to 31% (Table 3). The variability of the individual AUC 0 – t values was higher after rectal administration compared to oral administration (99 vs. 39%, Table 1). Compared to oral administration, the maximum concentrations after rectal administration were reduced by a factor of four (Table 3) and occurred on average 1.9 h later than after oral administration (Table 1). The comparison rectal versus oral administration of denaverine hydrochloride agreed with what is generally expected using the rectum as an absorption site: a decreased rate and extent of bioavailability combined with a

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higher variability in the pharmacokinetic parameters (de Boer et al., 1982, 1984; Fischer, 1986; van Hoogdalem et al., 1991a,b). Incomplete absorption probably due to the low absorption surface area of the rectum rather than degradation of denaverine in the rectum was obviously the reason for the observed reduced bioavailability of denaverine after rectal administration since chemical stability of denaverine was ¨ guaranteed in the pH range of interest (Gober et al., 1981) and enzymatic activity in the rectal fluid, if it exists at all, is negligible (Lippold, 1984). A frequently cited advantage of rectal administration is the partial avoidance of first-pass metabolism (de Boer et al., 1979; Cid et al., 1986; Sanders et al., 1986; Hellstern et al., 1987; Babul and Darke, 1993). Here, the mean curve of MD 6 after rectal administration of denaverine hydrochloride solution increased slowly, showed a broad maximum (between 4 and 12 h) and was markedly lower than after intravenous or oral administration (Fig. 3). Setting the point estimates of AUC 0 – t ratios for MD 6 and the parent compound against each other for the comparison rectal versus intravenous administration (10 vs. 10%, Table 3) and rectal versus oral administration (7 vs. 31%, Table 3) demonstrated clearly that first-pass metabolism could be reduced using the rectum as the absorption site. However, the limited absorption surface area seemed to be the predominant factor determining rate and extent of bioavailability after rectal administration. The reasonable absolute bioavailability of 37% of an oral solution of denaverine hydrochloride and the superior rate and extent of bioavailability after oral compared to rectal administration of aqueous solutions of denaverine hydrochloride suggested that with regard to rate and extent of bioavailability, the oral administration is a feasible alternative to the intravenous or rectal administration of denaverine hydrochloride.

3.3. In vivo characterisation of the suppository formulation Over the entire blood sampling period, the mean profile of denaverine after administration of the suppositories was lower than after administration of any of the aqueous solutions of denaverine hydrochloride (Fig. 2). The mean curve after rectal administration of the suppositories was characterised by a slow increase resulting in a low and broad maximum (3–10 h). Thereafter, the mean curve declined gently with a slight bump 24 h after administration reflecting irregularities in the individual profiles. The effect of the suppository formulation ¨ (Spasmalgan  -Zapfchen) on the bioavailability of denaverine could be summarised quantitatively as follows: In comparison to the rectal solution, the extent of bioavailability of denaverine was reduced to 42% (Table 3) when administered as the suppository formulation. The mean Cmax value was lower by a factor of three (Table 3) after

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administration of the suppository in comparison to the rectal solution and maximum concentrations occurred mostly 2–5 h later, whereby some subjects exhibited very late maximum concentrations 24 h after administration. In conclusion, the suppository formulation (micronised denaverine hydrochloride, particle size #50 mm, in Witepsol H15) was inferior to the rectal solution with regard to rate and extent of bioavailability. The most probable reason for these results seems to be the limited release of denaverine hydrochloride from the hard fat base Witepsol H15. Whether release and bioavailability of denaverine after administration as a suppository formulation could be improved by changing the suppository excipients or by changing the particle size of the denaverine hydrochloride incorporated into the suppositories is difficult to predict on the basis of the available data. The availability of a rectal formulation of denaverine as an alternative to an oral formulation is desirable as often when denaverine is indicated, nausea and discomfort in the gastrointestinal tract are also present. The low plasma concentrations of denaverine and the ¨ late t max after administration of Spasmalgan  -Zapfchen compared to intravenous and oral administration raise the question whether these low plasma concentrations and the slow rate of absorption are sufficient for the achievement of the desired therapeutical effects. On the one hand, it ¨ should be considered that Spasmalgan  -Zapfchen have been used successfully in therapy for more than 30 years. However, on the other hand, a randomised, double-blind, placebo controlled clinical study confirming these observations has not been carried out yet but is currently under consideration.

Acknowledgements The authors would like to acknowledge the financial support and co-operation of Apogepha Arzneimittel GmbH, Dresden, Germany in this project.

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