Gerhard Levy

Serum protein binding of drugs during and after pregnancy in humans

The serum protein binding of three weakly acidic drugs (salicylic acid, sulfisoxazole, and Phenytoin), one weak base (diazepam), and one steroid (dexamethasone) was determined in pregnant women at seven time periods during pregnancy and at two time periods post partum, as well as in a group of nonpregnant women of childbearing age. The serum free fraction values (ratio of concentrations, free to total drug) of all drugs rose during pregnancy, primarily after 15 wk of gestation, and remained elevated for at least 1 to 5 days post partum. Pregnancy had the greatest effect on protein binding of sulfisoxazole, diazepam, and salicylic acid. The magnitude of this effect is such that quantitatively significant changes in the pharmacokinetic and pharmacodynamic characteristics of certain drugs may be expected to occur during pregnancy (in addition to possible changes caused by other pregnancy‐related effects such as altered activity of drug‐metabolizing enzyme systems). All drugs but dexamethasone exhibited significant negative correlations between free fraction values and serum albumin concentrations during pregnancy. The serum protein binding of salicylic acid, but not the other drugs tested, was more extensive in nonpregnant women who were not taking oral contraceptives than in those who were.

Effect of plasma protein and tissue binding on the biologic half‐life of drugs

It is now generally appreciated that there can be pronounced interindividual differences in plasma protein binding of many drugs because of genetic,13 environmental (drug interaction),11 and pathologic7 factors and aging.1 Pharmacokinetic theory has been developed to relate quantitatively the effect of changes in plasma protein binding to changes in the elimination kinetics of drugs.8,14 In the case of drugs that are eliminated almost entirely by hepatic biotransformation with linear (apparently nonsaturable) kinetics not limited by organ perfusion rate, it has been shown that the total clearance (Cl) is directly proportional to the free fraction of drug in plasma (fp), i.e.,

A pharmacokinetic perspective on medicament noncompliance

Clinical Pharmacology and Therapeutics (1993) 54, 242–244; doi:10.1038/clpt.1993.143

Concentration- or effect-controlled clinical trials with sparse data

Clinical Pharmacology and Therapeutics (1994) 56, 1–8; doi:10.1038/clpt.1994.93

What are narrow therapeutic index drugs

Clinical Pharmacology & Therapeutics (1998) 63, 501–505; doi:

Protein binding of several drugs in serum and plasma of healthy subjects

The protein binding of phenytoin, propranolol, salicylic acid, warfarin, and bilirubin was determined in heparinized plasma and serum obtained from the same healthy adult subjects. There were no significant differences in the free fraction values of these compounds in plasma and serum. Addition of heparin to serum had no significant effect on protein binding. Contact with Vacutainer stoppers increased the free fraction of the weak base propranolol in serum and plasma but had no significant effect on the protein binding of the other, weakly acidic compounds tested. The lack of differences in the protein binding of phenytoin, salicylic acid, warfarin, and bilirubin in human plasma and serum is in contrast with the pronounced differences observed previously in rat serum and plasma.

Publication bias : its implications for clinical pharmacology

Clinical Pharmacology and Therapeutics (1992) 52, 115–119; doi:10.1038/clpt.1992.119

The Development of Pharmacodynamics as a Pharmaceutical Science: A Personal Perspective

It was a day in the early 1950sat the University of California School of Pharmacy in San Francisco (UCSF) when I saw my fellowundergraduate studentBert Ballard staring intently at a large, water-filled glassbeakercontaining goldfish. Responding to my expressed curiosity, he explained that the lateral nerve in goldfish controls the animals balance and that it is very similar to the eighth cranial (hearing) nerve in humanswhich does the same. Bert was studying the effectof the potentially ototoxic antibiotic streptomycin on balance in the fish under the guidance of Dr. Dufrenoy, a visiting French pharmacognosist. I thoughtthat the apparently off-balance goldfish were simply leaning into the curve (like a race car driver) as they circled in the beaker but kept my mouth shut. I forgot all about this encounter until several years later, but discuss moreaboutthis in a subsequent paragraph. When Harvey Whitney Jr. asked me to contribute an article to the 40th Anniversary Edition of The Annals, I reactedwithmixedfeelings. On one hand,I considerHarvey a friend, and I admirehis and his staffs accomplishments in makingand keeping The Annals a cutting-edge publication and, in my opinion, the mostvaluable journal for clinical pharmacists and of great valuealso for other pharmaceutical scientists and clinical pharmacologists. These were strongenoughreasonsto acceptHarveys invitation. On the otherhand, I am now78 yearsold and I havegiven away almost all of my professional library and discarded my files and records. I live in a small town (Sarasota, Florida) without a HealthSciences Library nearby, and the Internet is not of much help for recalling the old days. What finally convinced me to undertake this writing assignment was an email from Associate Editor Eugene Sorkin, who told me that it would be good if you could somehow impress upon our new practitioners and graduates that what they take for granted today has not always been that way.

The Pharmacist's Role in Product Selection

EARLIER THIS YEAR, there appeared a document titled A White Paper on The Pharmacists Role in Product Selection, and stated to be a background and position paper issued by the Board of Trustees of the American Pharmaceutical Association. Perhaps I should call it the Apple White Paper but I shall refer to it simply as the White Paper. It is obviously impossible to comment here on all aspects of this lengthy and wide-ranging document, but it is important to deal at this meeting, which is devoted to the problem of drug product equivalence, with at least the essentials of those statements which pertain directly to therapeutic issues. It is claimed in the White Paper that:

A Training Program in Clinical Pharmacokinetics

CLINICAL PHARMACOKINETICS has been defined as a health sciences discipline which deals with the application of pharmacokinetics to the safe and effective therapeutic management of the individual patient. It is now an important component of the formal instructional program in many schools of pharmacy and constitutes the basis of a new and growing health sciences specialty. The purpose of this article is to describe the training program in clinical pharmacokinetics at Buffalo at the undergraduate, Pharm.D. and post-Pharm.D. levels, with emphasis not only on the program content but also on its underlying philosophy. Since the quality and character of an academic program depend more on the faculty than on the formal content of the courses, and since the academic community in pharmaceutics is relatively small and its members in this country are well known to one another, I will identify my colleagues as I discuss our program and their role in it.