1 Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of the drug. This coincides with reduced drug effects through an unknown mechanism. 2 The effect of interferon-induced acute inflammation on the pharmacokinetics and electrocardiogram of verapamil (20 mg kg À1 , p.o.) and nifedipine (0.1 mg kg À1 , i.v.) was studied in SpragueDawley rats. 3 The effect of both acute and chronic inflammation on radioligand binding to cardiac L-type calcium channels was also investigated. 4 Acute inflammation resulted in increased plasma concentration of verapamil but had no effect on that of nifedipine. Verapamil binding to plasma proteins was unaffected. 5 As has been reported for humans, the increased verapamil concentration coincided with a reduction in the degree to which PR interval is prolonged by the drug. The effect of nifedipine on PR interval was also reduced by inflammation. 6 Maximum binding of 3 H-nitrendipine to cardiac cell membrane was significantly reduced from 63.272.5 fmol mg À1 protein in controls to 46.472.0 in acute inflammation and from 66.872.2 fmol mg À1 protein in controls to 42.272.0 in chronic inflammation. 7 Incubation of the normal cardiac cell membranes with 100 and 1000 pg ml À1 of rat tissue necrosis factor-a did not influence the binding indices to the calcium channels. 8 Our data suggest that the reduced calcium channel responsiveness is because of altered binding to channels.

The peroral (po) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first‐pass effect after po dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first‐pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (ic), and intraperitoneal (ip) routes of administration were compared to that for an intravenous (iv) dose (in each case a dose of 6 mg kg−1 was given) using adult male Sprague–Dawley rats (249–311 g, n =6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after iv dosing was 10·3 mL min−1 kg−1. The nifedipine blood‐to‐plasma ratio was found to be about 0·59. Therefore, the systemic blood clearance of nifedipine was about 17·5 mL min−1 kg−1; which, compared to the hepatic blood flow of rats (55 to 80 mL min−1 kg−1) showed that nifedipine is poorly extracted by the liver (0·22≤EH≤0·32). The mean absolute bioavailabilities of the po, ip, and ic doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first‐pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat. © 1997 John Wiley & Sons, Ltd.

Extended-release morphine formulations are widely used in the management of chronic pain. Avinza (morphine sulfate extended-release [MSER, Morphelan]) is a new, once-a-day, extended-release morphine formulation designed to reach target concentrations rapidly and maintain concentrations throughout a 24-hour period. The primary objective of this study was to compare the 24-hour steady-state pharmacokinetic (PK) profiles of morphine and its metabolites (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]) following ingestion of MSER once-a-day and MS Contin (controlled-release morphine sulfate [CRM]) twice-a-day in patients with chronic moderate-to-severe pain. Ten patients with chronic moderate-to-severe pain were recruited into an open-label, multiple-dose, nonrandomized, two-period, single-center study. All patients were stabilized for a minimum of 7 days on a twice-daily dose of CRM associated with an optimal balance between pain control and side effects. Patients were then switched to the closest equivalent once-daily dose of MSER for a minimum of 10 days. Twenty-four hour steady-state PK profiles were obtained on the last day of each treatment period and additional clinical and safety assessments were performed. PK data were normalized to a 100-mg total daily dose prior to statistical analysis. Nine of the 10 patients completed the entire study. MSER and CRM demonstrated similar bioavailability (AUC) of morphine and its metabolites. Compared to CRM, MSER demonstrated a 19% lower maximum concentration (C(max)), a 66% higher minimum concentration (C(min)), and a 44% lower peak-to-trough fluctuation (%FI) over the 24-hour period. In addition, MSER maintained concentrations above 50% and 75% of the C(max) longer than CRM. Clinical efficacy and safety were comparable for MSER and CRM. Once-daily MSER approaches maximum morphine concentration more quickly, approximates maximum concentration longer, and demonstrates less fluctuation in morphine concentration during a 24-hour period than CRM dosed twice daily. The pharmacodynamic implications of this profile deserve further study.

The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.