Peter G. Welling

Influence of food and diet on gastrointestinal drug absorption: A review

The literature concerning the influence of food, and also fluid volumes, on drug absorption is reviewed. In most cases, the absorption of drugs from the gastrointestinal tract is reduced or delayed by food. However, some drugs are unaffected by food, while the absorption of a small number of drugs is increased. Observed effects of food on drug absorption are the net result of various factors, including the influence of food on gastrointestinal physiology and also physicochemical interactions between drugs, drug dosage forms, and dietary components. The intensity of food-drug interactions may be influenced by the type of food and by the time interval between eating and drug administration. Large coadministered fluid volumes tend to promote drug absorption. The clinical significance of changes in drug bioavailability due to these factors is discussed.

Interactions affecting drug absorption.

SummaryThe influence of drug-drug and drug-food interactions affecting the absorption of orally administered medication is reviewed. Drug-drug interactions can be classified in terms of indirect effects by one drug on gastrointestinal tract physiology influencing the absorption of other drugs, or direct interactions involving altered pH, adsorption, absorption, or chelation. Most, but not all, drug-drug interactions result in reduced or delayed systemic drug availability.Drug-food interactions may result in reduced, delayed, or increased systemic drug availability. The absorption of only a small number of drugs is unaffected by concomitant food intake. The degree of interaction and whether it positively or negatively affects drug absorption depends on a number of factors including the physical and chemical nature of the drug, the formulation, the type of meal, and the time interval between eating and dosing.Mechanisms of drug-food interactions are not well characterised. They clearly involve both direct and indirect factors in a similar fashion to drug-drug interactions, but indirect factors probably predominate. Reduced or delayed drug absorption is generally attributed, at least in part, to delayed stomach-emptying due to food. Increased absorption may also result from delayed stomach-emptying facilitating greater drug dissolution before it passes from the stomach into the small intestine. Increased bioavailability of some drugs, e.g. propranolol, metoprolol and labetalol, may be related to reduced presystemic clearance.The potential clinical implications of drug-drug and drug-food interactions must be taken into account with oral medications in order to minimise variations in systemic drug availability and hence in clinical efficacy.

Protein binding of antimicrobials: clinical pharmacokinetic and therapeutic implications.

SummaryBinding of antimicrobial agents to serum proteins, and to extravascular tissues, affects their distribution, elimination, and pharmacological activity. The extent of binding of drugs to serum proteins is both drug concentration and protein concentration dependent. However, changes in drug concentrations within therapeutic range have little effect.Drug-protein binding may be reduced by the presence of other drugs, and also by endogenous substances. The latter may be important in cases of impaired renal or hepatic function and in disease states associated with elevated free fatty acids. The greatest reductions in protein binding are observed with drugs that are normally highly bound.Equations are presented to describe the influence of the binding of drugs to serum proteins and tissues on the percentage of drug which is free in the body, the concentration of free and total drug in serum, and the apparent distribution volume of drug in the body. Changes in the percentage bound to serum proteins tend to produce curvilinear changes in the various values with the greatest changes occurring with highly bound drugs (greater than 80% binding). Changes in the percentage bound to tissues tend to produce linear changes in all values except the apparent drug distribution volume. Small changes in tissue binding of highly bound drugs cause marked changes in apparent distribution volumes.Although tissue and extravascular fluid drug levels are primarily influenced by the free drug levels in serum, calculation of actual tissue levels is complicated by variable binding characteristics of specific tissues and tissue fluids, and also by the lipophilic nature of the drug.Renal elimination of antimicrobial agents is markedly influenced by serum protein binding if the major elimination mechanism is glomerular filtration. Serum protein binding has little effect on drug elimination in cases of elimination by renal tubular secretion and hepatic extraction. As in the case of distribution, renal clearance and hepatic extraction may be a function of both protein binding and drug lipophilicity.A drug which is bound to serum proteins has no antibacterial activity in vitro. However, binding of drugs to serum proteins in vivo has major clinical significance only when levels of free drug are reduced to values below the minimum inhibitory concentrations of susceptible micro-organisms. In many cases, high protein binding may be compensated for by greater intrinsic antimicrobial activity of lipophilic drugs.

Influence of diet and fluid on bioavailability of theophylline

The influence of various test meals, and of fluid volumes, on the bioavailability of theophylline from asolid dosage form has been studied in healthy male volunteers. Absorption of drug was faster after dosing immediately following a high protein meal than after a high fat or a high carbohydrate meal. Absorption from a solution was faster than from asolid dosage form in all treatments; areas under serum level time curves after dosing were also significantly higher up to 12 hr. Areas up to 12 hr after dosing also tended to be higher after the high protein meal and after dosing with 500 ml water on an empty stomach than after other solid dose treatments.

Bioavailability of Tetracycline and Doxycycline in Fasted and Nonfasted Subjects

The influence of various test meals and fluid volumes on the relative bioavailability of commercial formulations of doxycycline hyclate and tetracycline hydrochloride was studied in healthy human volunteers. Serum levels of tetracycline were uniformly reduced by approximately 50% by all test meals, whereas serum levels of doxycycline were reduced by 20%. The reduction of tetracycline serum levels will likely be of clinical significance. The bioavailability of each drug was almost identical from an oral solution and from capsules in fasted subjects. The rate of doxycycline absorption was reduced when capsules were administered with a small volume of water, but the overall efficiency of absorption of both drugs was essentially independent of co-administered fluid volume. The use of 8-h serum data provides a reliable estimate of drug bioavailability for tetracycline and, to a lesser extent, for doxycycline.

Reduction in oral penicillamine absorption by food, antacid, and ferrous sulfate.

Plasma levels of penicillamine, urinary recovery of penicillamine and its oxidized metabolites, and urinary excretion of copper were examined afier single 500‐mg oral doses of penicillamine to six healthy men. Penicillamine was given after an overnight fast, a standard breakfast, and after antacid and ferrous sulfate. Following the fasting dose, the mean peak plasma level of 3.05 µg/ml developed at 3.8 hr and the drug was cleared from plasma with a t½ of 2.1 hr. Penicillamine levels were reduced to 52%, 35%, and 66% of those from the fasting dose after food, ferrous sulfate, and antacid. The rates of penicillamine appearance and disappearance from plasma were essentially treatment independent. There were good correlations between urinary recovery of total penicillamine (r = 0.875), between urinary copper excretion (r = 0.758) and the penicillamine plasma concentration AUCs. The availability of oral penicillamine is very susceptible to interactions with other substances. Further studies may be necessary to assess the full clinical significance of these interactions.

Clinical pharmacokinetics of co-trimoxazole (trimethoprim-sulphamethoxazole).

The combination trimethoprim-sulphamethoxazole (co-trimoxazole) is used clinically for the treatment of a variety of infections due to Gram-positive and Gram-negative organisms; particularly for urinary and respiratory tract infections. While both trimethoprim and sulphamethoxazole are mainly bacteriostatic when used alone, their combined effect tends to be bactericidal. Synergism is due to sequential blockade at two separate steps in bacterial folate metabolism, resulting in inhibition of deoxyribonucleic acid synthesis.The optimum concentration ratio of trimethoprim sulphamethoxazole for a bactericidal effect varies between 1:5 and 1:40, which is consistent with their relative minimum inhibitory concentration (MIC) values against susceptible organisms. The combination is administered principally by the oral route, although it is also given parenterally and rectally. A single oral dose of 160mg trimethoprim and 800mg sulfamethoxazole gives peak serum levels at approximately 4h of 1.2 to 2μg/ml trimethoprim and 26 to 63μg/ml sulphamethoxazole. After repeated 12-hourly doses, minimum serum levels are 1.3 to 2.8μg/ml and 32 to 63μg/ml for trimethoprim and sulphamethoxazole respectively. The high concentration of sulphamethoxazole in serum relative to that of trimethoprim is due to the greater tissue penetration of trimethoprim. The high sulphamethoxazole:trimethoprim concentration ratio in serum does not always occur in extravascular tissues. However, this is partially compensated for by the high bacteriostatic activity of trimethoprim alone in tissues.The 2 compounds are bound to plasma proteins to similar extents. Both trimethoprim and sulphamethoxazole obey first order absorption, distribution, and elimination kinetics. The disposition of sulphamethoxazole in the body after oral doses has been described in terms of one-compartment model kinetics, while both one-compartment and two-compartment model kinetics have been used to describe the disposition of trimethoprim.Both compounds are cleared from the body predominantly via the kidneys, sulphamethoxazole being excreted mainly in the acetylated form. Average elimination half-lives of trimethoprim and sulphamethoxazole are 11 and 9h respectively, although there is considerable individual variation in these values. The clearance of both compounds is not markedly affected by declining renal function until creatinine clearance falls below 30ml/min. In severe renal failure, the elimination half-lives of both drugs may increase to 45 to 60h and adjustment of dosage is necessary to avoid renal toxicity. Both trimethoprim and sulphamethoxazole appear in bile at concentrations similar to those observed in serum, although the sulphamethoxazole:trimethoprim concentration ratio in bile is somewhat less than that in serum.Trimethoprim and sulphamethoxazole give rise to only occasional side effects, which are characteristic of the individual compounds. Principal reactions are those associated with sulphonamide sensitivity, and renal toxicity in patients with impaired renal function. Anaemia due to impaired folate metabolism may be a problem in some patients.

Pharmacokinetics of Alcohol Following Single Low Doses to Fasted and Nonfasted Subjects

The absorption and elimination characteristics of alcohol have been studied in healthy fasted and nonfasted human volunteers using low single doses. In non-fasted subjects, carbohydrate reduced overall alcohol bioavailability by about 96 percent, compared to 90 per cent for fat and 75 per cent for protein. Inhibition of absorption in nonfasted subjects appeared to be due to less alcohol being available for absorption rather than a reduced absorption rate. Serum alcohol levels in fasted subjects were interpreted in terms of both first-order and zero-order absorption followed by first-order elimination. Of the two proposed models, that utilizing zero-order absorption provided a marginally better fit to observed data.

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function

The pharmacokinetics of 14C‐labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 μCi/ml/mg) after a high‐carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t½values of 2.0 to 5.0 hours, with no relationship between CLCRand glyburide clearance. One subject with severe renal impairment (CLCR= 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t½of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.

Bioavailability of Oral and Intramuscular Phenobarbital

The absorption of phenobarbital was compared in healthy adult subjects after oral and intramuscular therapeutic doses. Serum levels of phenobarbital were determined for 21 days after dosing by means of radioimmunoassay. Serum levels were similar from both dosage routes, with peak levels occurring at 1-3 hours after dosing and then declining slowly with an elimination half-life of about 90 hours. The overall efficiency of phenobarbital absorption from intramuscular doses was approximately 80 per cent of that from equivalent oral doses. Except in cases where oral dosing is not appropriate, there is no clinical advantage in giving phenobarbital intramuscularly to adult patients.