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Herbal medicinal products have to meet comparable standards concerning the assessment of efficacy, safety and (bio)pharmaceutical quality as chemically defined synthetic drugs. However, these requirements are not fulfilled for many herbal products so far, particularly regarding in vitro dissolution and in vivo bioavailability. The necessity of in vivo studies for a biopharmaceutical characterisation of the products depends on the solubility/permeability properties of the active drug ingredient as well as dissolution behaviour of the dosage form. Also, in the case of herbal medicinal products, a waiver of in vivo BA/BE studies is recommended as long as the active ingredient is highly soluble according to the Biopharmaceutics Classification System and dissolution of the dosage form takes place rapidly (>85%/20 min) in physiological buffer systems (pH 1-8).

The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH-dependent differences in the in vitro release properties of the two dosage forms.This was a randomized, open, 4-way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat OROS or Slofedipine XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC-MS/MS method. Calculation of pharmacokinetic parameters was conducted model-independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat-bottomed glass vessels, with various buffer systems covering the entire physiological pH-range of the gastrointestinal tract.After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,infinity) was slightly lower for Slofedipine XL compared with Adalat OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine XL compared with Adalat OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine XL which resulted in lag-times of more than 15 h in 15 out of 24 subjects. Owing to this lag-time under fed conditions the relative bioavailability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 h.In this study a dosage form-dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine XL and Adalat OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine XL is administered after a high-fat breakfast may be explained by the formulation properties. Slofedipine XL is an erosive tablet with an acid resistant coating whereas Adalat OROS is designed with an osmotic push-pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push-pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.

The study was conducted to investigate the pharmacokinetics and relative bioavailability of clindamycin after administration of two oral clindamycin HCl formulations. A new tablet preparation containing 600 mg clindamycin (Clinda-saar 600, test) was compared to a marketed capsule containing 300 mg clindamycin (Sobelin 300, reference). Both preparations revealed comparable in vitro dissolution profiles with high batch conformity and homogeneity. Twenty healthy male volunteers received single doses of 600 mg clindamycin (test: 1 tablet, reference: 2 capsules) in an open, randomized, two-period crossover design. Blood samples were drawn up to 14 h p.a. and clindamycin plasma concentrations were measured using a sensitive and specific HPLC-UV method. Pharmacokinetic characteristics were similar for both preparations, arithmetic mean values (standard deviation) were computed as: AUC(0-infinity) 12.2 (4.2) and 13.1 (4.6) microg x h/ml, Cmax 3.1 (0.8) and 3.4 (0.8) microg/ml, t(max) 0.83 (0.24) and 0.85 (0.34) h, t(1/2) 2.3 (0.4) and 2.3 (0.6) h for test and reference, respectively. Mean relative bioavailability (point estimate) was 93% for AUC and 91% for Cmax. 90% confidence intervals for AUC and Cmax were within the predefined bioequivalence acceptance limits. Bioequivalence of test and reference preparations could be demonstrated. Single doses of 600 mg clindamycin orally were well tolerated without relevant differences between both preparations.

Two extended release (ER) formulations of morphine sulphate (30 mg each), Oramorph SR (test) and a marketed reference formulation (MST Mundipharma Retardtabletten), were investigated for their relative bioavailability at steady-state:The study was designed as a single-centre, open-label, two-period crossover, pharmacokinetic comparison in 28 healthy male volunteers and was completed in 23 subjects. The determination of morphine and its metabolite morphine-6-glucuronide in plasma was done by HPLC with electrochemical detection after solid-phase extraction.Under steady-state conditions in the first dosing interval, mean maximum plasma concentrations for morphine were 19.1 ng/ml (CV% 41) for Oramorph SR 30 mg and 19.1 ng/ml (CV% 33) for MST-30 Mundipharma Retardtabletten. Geometric mean AUC(0-12) values were calculated as 108 ngxh/ml (CV% 40) for Oramorph SR 30 mg and as 118 ng x h/ml (CV% 30) for the reference formulation. The plasma concentrations of the major metabolite, morphine-6-glucuronide, were found to be generally in a higher range compared to the parent compound. The 90% confidence intervals of test to reference ratios calculated for all relevant parameters (AUC, C(max), PTF) for both the parent compound and morphine-6-glucuronide were all within the limits of 80 - 125%. The most frequent adverse events (AE10%) during Oramorph SR 30 mg treatment were headache (36%), dizziness (18%), nausea (21%), vomiting (21%) and pruritus (11%). During treatment with MST-30 Mundipharma Retardtabletten, the most frequent AEs were headache (29%), dizziness (13%), nausea (29%) and vomiting (29%).The results demonstrate bioequivalence of Oramorph SR 30 mg and MST-30 Mundipharma Retardtabletten.

The effect of drug interactions with other drugs, excipients and gastrointestinal contents on their oral absorption and systemic availability have been extensively investigated over the past 50 years. These interactions can be classified as direct interactions between the drug and other drugs or components in the formulation, e.g., excipients in the gastrointestinal tract altering the drugs’ thermodynamic activity for absorption or, alternatively, the effects may be indirect through alteration of gastrointestinal transit, gastrointestinal secretions, or gastrointestinal/hepatic metabolism or elimination. Recently attention has been directed to metabolism interactions in the liver and even more recently in the gastrointestinal mucosal tissue. These interactions can be caused by direct inhibition of enzyme metabolism or enzyme induction, resulting in changes in the absorption rate and leading to altered oral bioavailability. These metabolic effects also can be indirect, through the position dependence of metabolizing enzyme levels in the gastrointestinal tract; consequently transit changes can alter metabolic profiles and systemic availability. Recent interest has been directed to carrier-mediated absorption, where drug interactions can occur through competition for carrier(s) responsible for absorption and, finally, it has been proposed that the P-glycoprotein exporter may be responsible for some of the observed drug interactions and nonlinear absorption effects. This review will focus on examples of the various types of mechanistic interactions noted above. The interaction of drugs with foods, a very important component in drug regulation today, is reviewed elsewhere in this volume. A more comprehensive survey of relevant drug-drug interaction than can be covered in this review can be found in Table 1.

Oral antidiabetic drugs are widely used in the treatment of diabetes mellitus and are effective in controlling blood glucose levels. These drugs are of several distinct types with different modes of action and include sulfonylureas, biguanides and α-glucosidase inhibitors. The sulfonylurea antidiabetic drugs include acetohexamide, acetylcarbutamide, carboxytolbutamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, metahexamide, tolazamide and tolbutamide. The structural formulas of some of the important antidiabetic agents are given in Fig. 1.

To investigate the influence of certain drugs and agents upon collagenolytic activity in human cartilage, homogenized articular cartilage from osteoarthritic human hips was incubated with dexamethasone, diclofenac, indometacin, phenazone, phenylbutazone, tiaprofenic acid, sulfasalazine, penicillamine, chloroquine, cysteine and a glycosaminoglycan-peptide complex (DAK-16). Collagenolytic activity was quantitated by the release of soluble hydroxyproline-containing peptides. The presence of collagenase in osteoarthritic cartilage was proved by the typical 75:25 cleavage products of type I collagen. Enzymatic collagen breakdown was found to be inhibited by chloroquine, cysteine, DAK-16, and sulfasalazine whereas the other tested agents had no significant effect. The inhibitory potency of chloroquine at therapeutical dose levels may be of pharmacological and therapeutic relevance.

Human recombinant interleukin-1 alpha or beta was injected intraarticularly several times into the knee joints of rats and hens at different dosages (50-2000 ng) and intervals. No loss of cartilage detectable by width of the radiological joint space and no degenerative changes of subchondral bone could be observed during 16 weeks using X-ray analysis. The macroscopical examination of articular cartilage of hens after this period and of rats after one year showed no morphological cartilage damages. These data suggest that human recombinant Il-1 alpha and beta alone may not be sufficient to induce a progressing osteoarthritic process in these animals.