Preclinical evaluation of pharmacokinetic–pharmacodynamic rationale for oral CR metformin formulation

https://doi.org/10.1016/S0168-3659(00)00374-6Get rights and content

Abstract

We examined the pharmacokinetic (PK) and pharmacodynamic (PD) rationales to develop controlled release (CR) formulations of metformin. Unrestrained diabetic rats received the drug as intravenous bolus (i.v.), oral solution (p.o.), intra-duodenal bolus, 4-h infusion, or intra-colonic bolus. In addition, we developed two CR-gastroretentive dosage forms (CR-GRDF) that released the drug over 3 or 6 h (in vitro), and retained in the rats’ stomach for 8–10 h. Metformin exhibited flip-flop PK. The colonic absorption was low but sustained and was associated with highly variable glucose-lowering effects, thus providing a PK rationale to develop CR-GRDF. In addition, the glucose-lowering effect was greater following p.o. vs. i.v. administration, despite equivalent AUC, indicating a first pass PD effect, thus, adding a PD rationale to develop metformin CR-GRDF. When administered to the diabetic rats, CR-GRDFs produced bioavailability and extent of glucose-lowering effects that were similar to those of the duodenal infusion and p.o. metformin administration. These findings are attributed to the adsorption of metformin to the intestine that yields slow and prolonged absorption even following p.o. administration of drug solution. The data indicates that unless the CR formulation could significantly extend the absorption period, it is not likely to improve glucose-lowering efficacy.

Introduction

Metformin is a biguanide glucose-lowering agent that has been widely used for management of NIDDM [1], [2]. Unlike other biguanide drugs, metformin does not induce lactic acidosis. However, current metformin therapy is suboptimal as it is associated with a high incidence of gastrointestinal side effects, seen in about 30% of patients [3], and the drug is commonly administered at high doses (as oral tablets) 2–3 times per day, to achieve effective glucose-lowering treatment. Since the pharmacological mechanism of action of metformin differs from that of the other antidiabetic drugs, it has a very important role in NIDDM treatment. There are continuing efforts to improve its pharmaceutical formulation in order to optimize therapy. These efforts have been focused on the development of oral sustained release (SR) preparations [4], [5], [6], [7], as well as more sophisticated controlled release (CR) gastroretentive dosage forms [8]. Currently, there is an increased interest in developing new metformin formulations because the metformin US patent expires this year.

Metformin has properties of a strong base (pKa 11.5) and is protonated at physiologic pH. The ionized metformin has a tendency to adsorb to the negatively charged intestinal epithelium, thus affecting the drug absorption pattern. The high polarity of this drug also dictates its fast renal elimination with no significant metabolism. In addition to these unique pharmacokinetic (PK) properties, the pharmacodynamics (PD) of metformin is rather complex and does not follow a direct relationship between plasma drug concentration and magnitude of effect [9], [10]. For instance, we have found that augmented effects were produced when metformin was administered via the GI tract in comparison to i.v. bolus despite similar systemic exposure to the drug (AUC) [11]. These PK and PD complexities may directly affect the efficacy of a CR formulation. In addition, the rate and site of drug release from the pharmaceutical dosage form may also influence the magnitude and duration of the pharmacological response [12], [13]. Therefore, an essential step prior to the development of advanced CR preparations should be to establish a biological rationale that takes into account both the PK and PD properties of the drug [14]. The present investigation was aimed to provide this information, and to assess whether optimization of metformin therapy may be accomplished by using oral CR drug delivery systems.

A conventional oral SR formulation releases most of the drug content at the colon, which requires that the drug will be absorbed from the colon. As there are indications that metformin has poor colonic absorption in healthy human subjects [15], [16], it is important to assess whether the absorbed amount is sufficient to produce effective glucose-lowering activity in a diabetic state. In the case of insufficient colonic absorption, clinical advantage may be accomplished by a CR-gastroretentive dosage form that is retained in the stomach and produces a constant input of the drug to the sites of absorption at the upper part of the gastrointestinal (GI) tract. In this work, we developed CR-gastroretentive dosage forms of metformin and assessed their PK and PD in comparison to other modes of drug administration. To accomplish this, we employed a commonly used preclinical NIDDM model of streptozotocin-induced diabetes in rats. The CR-gastroretentive dosage forms were based on polymeric slow release matrix tablets of the metformin that are retained for several hours in rat stomach.

Section snippets

Materials

Metformin hydrochloride was kindly provided by Teva Pharmaceutical Industries, Ltd., Netanya, Israel. Phenformin hydrochloride was purchased from Sigma Israel Chemicals Ltd., Rehovot, Israel. All other reagents used in this study were of analytical or HPLC grade.

Animals

Male Sabra rats (weighing 200–250 g, Animal Breeding Unit, The Hebrew University of Jerusalem, Israel) were used in this study. The animals were housed under standard conditions with a 12-h light/dark cycle with free access to water and

I.v. vs. p.o. administration

The pharmacokinetic and pharmacodynamic data following intravenous and p.o. bolus modes of metformin administration are presented in Fig. 1, Fig. 2. The rate of elimination of metformin as determined by the log terminal slopes following the two modes of administration are distinctly different (0.31±0.06 h−1 and 0.57±0.08 h−1 for p.o. and i.v. bolus, respectively, P<0.001). This difference indicates that the pharmacokinetics of metformin following oral administration is characterized by

Discussion

Earlier studies examined the PK profile of oral sustained release dosage forms of metformin [4], [5]. There is a pharmaceutical challenge in developing such dosage forms due to the high dose of metformin used clinically. Since regular metformin tablets contain 500–1000 mg of the drug, the dimensions of the tablet are close to the upper limit of the size that is plausible for patient intake. Due to the high water solubility of the drug, a considerable amount of polymeric excipients would be

Conclusions

The rat model was found to be an effective strategy for the evaluation of the PK and PD of CR-gastroretentive dosage forms, thereby providing a means to assess the PK and PD rationale to develop these formulations in order to optimize drug treatment. Although initially there seemed to be both a PK and a PD rationale to develop such formulations, the actual findings indicate that the differences in input rate of the drug to the upper GI region did not significantly affect the extent of metformin

Acknowledgements

This work is part of D. Stepensky’s Ph.D. dissertation. Dr. Amnon Hoffman and Prof. Michael Friedman are affiliated with the David R. Bloom Center for Pharmacy.

References (22)

  • A. Hoffman

    Pharmacodynamic aspects of sustained release preparations

    Adv. Drug Del. Rev.

    (1998)
  • N. Vidon et al.

    Metformin in the digestive tract

    Diabetes Res. Clin. Pract.

    (1988)
  • C.J. Dunn et al.

    Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus

    Drugs

    (1995)
  • C. Bailey et al.

    Metformin

    N. Engl. J. Med.

    (1996)
  • Glucophage Prescription Information

    (1999)
  • M. Noel

    Kinetic study of normal and sustained release dosage forms of metformin in normal subjects

    J. Int. Biomed. Data.

    (1980)
  • P. Pentikainen

    Bioavailability of metformin. Comparison of solution, rapidly dissolving tablet, and three sustained release products

    Int. J. Clin. Pharmacol. Ther. Toxicol.

    (1986)
  • K.H. Yuen et al.

    Relating in vitro/in vivo data of two controlled-release metformin formulations

    Drug Dev. Ind. Pharm.

    (1999)
  • K. Fujioka et al.

    Once daily dosing of a metformin extended release (Met-XR) formulation: effects on glycemic control in patients with type 2 diabetes currently treated with metformin

  • G. Gusler et al.

    Metformin (GR) gastric retentive tablets: GI transit and pharmacokinetics in healthy volunteers

  • P. Marchetti et al.

    Plasma biguanide levels are correlated with metabolic effects in diabetic patients

    Clin. Pharmacol. Ther.

    (1987)
  • Cited by (131)

    View all citing articles on Scopus
    View full text