Quantifying the 'Hidden' Lactose in Drugs Used for the Treatment of Gastrointestinal Conditions

P. Eadala; J.P. Waud; S.B. Matthews; J.T. Green; A.K. Campbell

Disclosures

Aliment Pharmacol Ther. 2009;29(6):677-687. 

In This Article

Abstract and Introduction

Abstract

Background: Lactose intolerance affects 70% of the world population and may result in abdominal and systemic symptoms. Treatment focuses predominantly on the dietary restriction of food products containing lactose. Lactose is the most common form of excipient used in drug formulations and may be overlooked when advising these patients.
Aim: To identify and quantify the amount of lactose in medications used for the treatment of gastrointestinal disorders and to identify 'lactose-free' preparations.
Methods: Medications used for the treatment of gastrointestinal disorders were identified from the British National Formulary (BNF). Their formulation including excipients was obtained from the Medicines Compendium. The lactose content and quantity in selected medications was measured using high-performance liquid chromatography (HPLC).
Results: A wide range of medications prescribed for the treatment of gastrointestinal conditions contain lactose. We have quantified the lactose content in a selection of medications using HPLC. Lactose is present in amounts that may contribute towards symptoms. Lactose-free alternatives were also identified.
Conclusions: Lactose is present in a range of medications and may contribute towards symptoms. This may not be recognized by the prescribing doctor as excipients are not listed in the BNF, and the quantity of lactose is not listed on the label or in the accompanying manufacturer's leaflet.

Introduction

Lactose is a disaccharide that consists of galactose and glucose molecules bonded through a β1-4 glycosidic linkage (Figure 1). Lactose makes up around 2-8% of the solids in milk and 1 mL of milk contains 47.2 mg of lactose.[1,2]

Figure 1.

Lactose: galactose and glucose molecules bonded through a β1-4 glycosidic linkage.

The enzyme lactase-phlorizin hydrolase, expressed in the villus enterocytes of the small intestine, is responsible for the hydrolysis of lactose. Lactase activity is high and vital during infancy, but in most mammals, including a majority of humans, it declines after weaning.[3,4] In adult life, lactase activity is at a variable level, determined by genetic predisposition, ethnicity, gastrointestinal (GI) disorders or infections.[3,4] Congenital lactase deficiency is caused by a distinct mutation in the coding region of the lactase gene which results in a severe GI disorder of infants that is rare and inherited in an autosomal recessive manner.[4,5] Adult-type hypolactasia is far more common and is also known as 'lactase nonpersistence' or 'lactose intolerance' (LI). The primary form is an autosomal recessive condition resulting from the physiological decline in activity of the lactase enzyme in intestinal cells after weaning.[4] The frequency of lactase nonpersistence varies significantly in different populations. The prevalence is above 50% in South America, Africa and Asia, reaching almost 100% in some Asian countries. In the US, the prevalence is 15% among whites, 53% among Mexican-Americans and 80% in the Black population. In Europe, it varies from around 2% in Scandinavia to about 70% in Sicily. Australia and New Zealand have prevalence of 6% and 9% respectively.[3,6] In the UK, up to 9% of the indigenous adult population (5.4 million individuals) are lactose intolerant.[1]

Furthermore, lactose sensitivity varies from person to person and may change with age.[1,4] The secondary form of LI occurs as a result of GI conditions, e.g. coeliac disease or infections that involve the small intestine. LI should not be confused with milk allergy, the former is caused by a lack of enzyme lactase and the latter is an immune reaction to milk proteins, which affects 20% of patients with symptoms suggestive of LI.[7] Cow's milk protein allergy (CMPA) is the most common food allergy in early childhood with an incidence of 2-3% in the first year of life. The overall prognosis of CMPA in infancy is good with a remission rate of approximately 85-90%.[8]

In individuals with low lactase levels, any lactose that is ingested is not completely hydrolysed within the small intestine. As a result, it reaches the large intestine where bacteria metabolize it to produce gases such as hydrogen and methane as well as small peptides and toxins.[1,9] These cause abdominal and systemic symptoms including stomach cramps, bloating, flatulence, diarrhoea, muscle cramps and headache.[1,10,11,12,13] Also, unabsorbed lactose raises the osmotic pressure in the colon, preventing water reabsorbption and causing a laxative effect.[14] In addition to this osmotic effect, we have recently suggested a signalling mechanism for these effects.[15]

The direct measurement of lactase activity in biopsies from the small intestinal mucosa is the gold standard and the reference method for all other indirect methods.[16] However, this method is invasive, expensive and not readily available. Hydrogen breath testing (HBT) after oral administration of lactose is widely used in clinical practice because it is cheaper and more easily available. Studies that evaluated the validity of HBT in comparison with direct enzyme analysis determined its specificity and sensitivity in the range from 89-100% to 69%-100%, respectively.[17] A more recent diagnostic tool for adult-type hypolactasia is genotyping of two single nucleotide polymorphisms (SNPs) located about 14 and 22 kb upstream of the lactase gene (LCT-13910 C/T and LCT-22018 G/A).[18] In patients of European descent, the CC-13910 genotype was found to be almost completely associated with lactase nonpersistence (LI). Unlike HBT, the results of LCT genotyping are not influenced by factors such as incomplete fasting or antibiotic therapy. Use of the assay easily differentiates patients with primary hypolactasia from those with secondary hypolactasia and LI. The LCT genotyping together with breath hydrogen and methane analysis and recording clinical symptoms should be used as the 'current best practice' in the biochemical investigation of lactose sensitivity.[19]

Excipients are defined as the constituents of a pharmaceutical agent that is taken by or administered to the patient, other than the active substance.[20] They have a variety of purposes, including the improvement of appearance, bioavailability, stability and palatability of the product. Excipients frequently make up the majority of the mass or volume of oral and parenteral drugs. These pharmaceutical adjuvants are usually considered to be inert and are said to have no effect on the intended action of the therapeutically active ingredients.[20] They are listed in the Medicines Compendium (MC) but not in the British National Formulary (BNF) and are not generally quantified. Lactose is one of the most widely used excipients in the pharmaceutical industry.[21] There are many reasons for its popularity as lactose is perceived to be inert, relatively inexpensive and nontoxic. It is also chemically stable and has no tendency to react with the active ingredient or other components of a formulation.[21] Finally, it is very palatable providing sweetness without any after taste.[20,21] It has been estimated that lactose is a component of about 20% of prescriptions and 6% of over-the-counter medications.[22]

Many of the drugs used in the treatment of common GI conditions such as dyspepsia, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) contain lactose as an excipient. In patients with concurrent hypolactasia, the use of medications that contain lactose may be of clinical significance.

Aims

To identify and quantify the amount of lactose used as an excipient in medications that are taken for the treatment of GI disorders. To assess if alternative 'lactose-free' medications are available for hypolactasic patients with co-existing GI conditions.

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