Duane C. Bloedow

Pharmacokinetics of Diltiazem in Selected Animal Species and Human Beings

The absorption, distribution and elimination of diltiazem hydrochloride in rodent and canine species are reviewed. The drug is well absorbed but undergoes first pass metabolism after oral administration. Diltiazem is extensively distributed, and 52 to 81 percent is bound to serum protein, depending on the species studied. Diltiazem is metabolized in the liver by several pathways; deacetylation, N-demethylation, and O-demethylation are the primary degradative steps. The metabolites are excreted in urine and feces, indicating that biliary excretion occurs. There is some evidence for enterohepatic cycling. Diltiazem is rapidly eliminated (t 1/2 = 2.24 hours) in beagle dogs, and the relatively short half-life appears to be a result of the high level of plasma clearance (46.1 +/- 4.8 ml/min/per kg body weight). A comparison of the plasma diltiazem clearance with hepatic blood flow in the dog indicates that the drug is eliminated at a rate dependent on hepatic blood flow.

Serum Binding of Diltiazem in Humans

Abstract: Diltiazem binding was measured by equilibrium dialysis in the serum of five healthy male subjects, aged 22 to 34 years, at seven serum diltiazem concentrations ranging from 0.03 to 2.06 μg/ml. The percentage of unbound diltiazem ranged from 19.6 ± 3.1 to 22.6 ± 4.1 (mean ± S.D.) and was independent of serum diltiazem concentration. Serum diltiazem binding was also examined in the presence of six drugs that might be used concurrently with diltiazem in patients being treated for cardiac disease. The percentage of unbound diltiazem was not influenced by digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin at therapeutic concentrations of these drugs over the therapeutic range of diltiazem.

Postburn Serum Drug Binding and Serum Protein Concentrations

The free fractions of diazepam, imipramine, lidocaine, meperidine, phenytoin, propranolol, and salicylic acid were determined in the serum of seven burn patients (25% to 80% of their skin surface burned) about one week after the burn and in three of the patients at about four weeks following the injury. Serum protein fractions were measured by electrophoresis, and alpha‐1 acid glycoprotein levels were determined. For the drugs that bind predominantly to albumin, the serum free fractions were greater in patients one week after the burn incident than in control subjects (diazepam, 0.055 vs. 0.017; phenytoin, 0.24 vs. 0.16; and salicylic acid, 0.69 vs. 0.32). The increase in free fraction for these drugs was attributed to the postburn decrease in serum albumin levels (2.2 vs. 4.4 g/dL, control). Imipramine, lidocaine, meperidine, and propranolol bind primarily to alpha‐1 acid glycoprotein. The free fractions for these drugs decreased one week following the burn (imipramine, 0.074 vs. 0.095; lidocaine, 0.17 vs. 0.35; meperidine, 0.37 vs. 0.48; and propranolol, 0.045 vs. 0.107), presumably in response to the increased alpha‐1 acid glycoprotein concentration (222 vs. 83 mg/dL, control). Diazepam, lidocaine, propranolol, and salicylic acid free fractions were still different from control values at four weeks after the accident.

Animal Models in the Study of Hepatobiliary Radiotracers

The last decade has been a time of active and fruitful interest in the development of hepatobiliary radiopharmaceuticals. In order to compare potential radiopharmaceuticals, define their biological behavior, and obtain data that would indicate behavior under clinical conditions, a variety of animal species and even isolated hepatocytes have been used. This chapter reviews the use of these animal models with respect to the type of information to be gained, advantages and disadvantages of the species under study, and correlation of data from one species to another as well as to the ultimate species, man.

Comparative study of 99mTc labeled hepatobiliary agents based on naphthalene and similar ring systems

A series of 99mTc complexes of naphthalene and naphthalene-like ring systems were evaluated pharmacokinetically as hepatobiliary imaging agents and compared to 131I-rose bengal and 99mTc-N-(2,6-diethylacetanilide)-iminodiacetate in rats and dogs. Although all complexes studied exhibited high specificity for biliary excretion, they varied widely in disappearance rate from blood and in biliary excretion. Complexes with 8-hydroxyquinoline-7-carboxylic acid and hydralazine were relatively lipophilic and were eliminated more slowly than 131I-rose bengal; complexes of iminodiacetic derivatives of naphthalene, N-(2-acetylnaphthyl)iminodiacetic acid N-(2-naphthylmethyl)iminodiacetic acid were more polar and were eliminated much faster. Renal excretion of the complexes was 5.6% or less except for that of the latter compound (18%). Plasma binding ranged from 51 to 98%.

Imaging, Pharmacokinetics, Dosimetry and Antitumor Effects of Radiolabeled Anti-Breast Cancer Antibodies in Mouse and Man

Breast cancer is the most common malignancy in females in the United States and the third most common cause of cancer death in the United States1. Despite the advances in molecular biology, mammographic screening and therapy, the mortality rate from breast cancer has not changed appreciably over the past 30 years1. There is no known cure for metastatic breast cancer. In fact, survival time from the diagnosis of metastatic disease in some recent trials is shorter than survival time reported in serie, from a decade ago. This has been attributed to the potential of increased drug resistance developing during adjuvant therapy. New treatment approaches are sorely needed. One new approach has been to use intensive doses of chemotherapy in conjunction with autologous bone marrow support as described in this monograph by Shpall2,3. Despite this treatment, the majority of patients experience disease progression and death.

In Vivo Studies of Radiolabeled Monoclonal Antibodies Mc5 and KC4 in Human Breast Cancer

Breast cancer is the most common malignancy in women in the United States, with over 130,000 new cases developing annually(1). Despite improved methods for early detection and treatment, the death rate from breast cancer in the United States has not changed over tbe past 25 years. Nearly all patients who die from breast cancer do so as a result of widespread systemic metastases. Metastatic breast cancer is difficult to detect early and impossible to cure with currently available treatment modalities.