Never Mind the Bullocks, Here's the Science (24 page)

Squealing Tyres

Let me get my Cranky Complaint about tyres-squealing-on-dirt off my chest.

You are watching a movie, and now it’s time for the chase sequence. The cars head onto a dirt road. But even though it’s a dirt road, the car tyres give off a squealing sound! Car tyres squeal only when they are being dragged across some solid surface such as bitumen or concrete, and tiny fragments of rubber are torn off the tyre. If no rubber fragments are torn off, there are no squealing sounds. On a dirt surface, the tyres simply slide across the dirt – there’s no squealing sound.

You can blame it all on Jack Donovan Foley (1891- 1967). He developed many of the sound effect techniques used in today’s movies. At the end of a movie, in the credits, look out for ‘Foley Sound’. These are the people (the ‘Foley artists’) who add sound to movies. Most Bollywood movies and many Italian movies are shot without any live sound being recorded at the time of filming – Foley artists add the sound later. Foley artists each have their own special individual armamentarium of apparati to make special sounds, e.g. watermelons or bamboo to make the sound of a fistfight more dramatic. They have a huge collection of surfaces and female shoes, so they can add, for example, the sound of a pair of stilettos walking across a variety of floor surfaces. And they will flap a pair of gloves to give a very good approximation of the sound of flapping wings.

They are also the dudes who unnecessarily add in the sound of squealing tyres to a car chase on dirt.

Cars Hard to Ignite

However, the Pinto was a very unusual case. In general, cars very rarely catch on fire.

So how do they make movie cars burst into flame?

One popular method is to ignite some dynamite inside a small waterbed full of petrol on the back seat of the car. The first explosion of dynamite scatters the petrol in all directions, so that at least some of it is in the desired 2-8% level. Almost immediately, a second explosion makes sure that it burns, if burning hadn’t already started with the first explosion.

It’s lucky for us that, unlike in Hollywood movies, cars do not burst into flames as soon as the wheels leave the ground. Think of how difficult it would be for your mechanic to service your car, if it burst into flames every time it was being lifted off the ground with the hydraulic hoist.

If cars did burst into flame at the slightest bump, imagine how careful you would have to be with shopping trolleys in the supermarket parking lot…

References

Donie, Mark, ‘Pinto Madness’,
Mother Jones
, 1 September 1977.

Schwartz, Gary T., ‘The Myth of the Ford Pinto Case’,
Rutgers Law Review
, Vol 43, 1991, pp 1013-1068.

Grapefruit Juice and Drugs
(C the Truth)

Grapefruit juice sounds like the kind of stuff that is unquestionably healthy. At the very least, it must contain vitamin C, which is surely a good thing.

True, but what most people don’t know is that grapefruit juice can interfere with some common medications.

Grapefruit 101

The grapefruit belongs to the citrus family. A mature tree can grow as high as 6 m, and produce up to 600 kg of fruit each year. At approximately 100-150 mm in diameter, this lemon-yellow fruit is larger than an orange. The pulp is usually a light yellow in colour, but can be pink or red. Like all citrus fruit, it has an acidic taste.

The grapefruit was first documented in 1750 by the Reverend Griffith Hughes as coming from Barbados in the Caribbean. It was taken to Florida in 1823 for further cultivation. In 1929, after a bit of crossbreeding, a grapefruit variety called the Ruby Red became very popular in the USA. Over the years, the grapefruit was crossbred to produce the orlando tangelo, the minneola and the
sweetie (oroblanco). Today, the USA (with a production of one million tonnes) and China (with half a million tonnes) account for about half the world’s annual production.

Accidental Discovery—1

The interactions of grapefruit juice with some medications first came to the attention of the medical community in 1991 with the publication of a paper in the prestigious medical journal
The Lancet.
Written by Dr David G. Bailey, from Ontario in Canada, the paper opens with three dry words, ‘A chance finding’, and then goes on to describe, in very academic language, that grapefruit juice can increase the levels of a certain drug in the blood. Those three words, ‘A chance finding’, do not even hint at the real story.

In their study, Dr Bailey and his fellow researchers wanted to find out whether alcohol had any effect on a new blood pressure drug called felodipine. But they wanted to keep the presence of the alcohol hidden from the volunteers.

Dr Bailey was given the job of disguising the strong burning taste of the pure alcohol. He was probably not the best person to ask, as he was both a non-drinker and an athlete—in fact, he was the first Canadian to run the four-minute mile. He and his wife spent the Friday night before the study began rummaging through the pantry and the fridge. He later said, ‘The only thing that covered the taste [of the alcohol] was grapefruit juice.’

So, thinking that grapefruit juice was inert as far as their study was concerned, they used it to mask the taste of the alcohol. Their study found that alcohol did not interact with the blood pressure drug felodipine.

The Bitter Truth About Grapefruit

Grapefruit juice has long been accepted as being unquestionably healthy. Common belief asserts it is rich in vitamin C, surely a good thing. This is true – however, the grapefruit has a dark side. Grapefruit juice can interfere with some common medications.

Accidental Discovery—2

However, they also discovered something weird—the drug levels in the blood of the volunteers were three times higher than expected!

The researchers contacted the drug company that supplied them, and asked if they had accidentally labelled 20 mg tablets as being 5 mg tablets. But an analysis of the tablets found them to contain, as advertised, 5 mg of felodipine.

So Dr Bailey did a mini-study on himself. The first day, he took felodipine with water, and sent a blood sample off for analysis. The second day, he took felodipine with grapefruit juice and, again, sent off a blood sample.

His body told him that his blood levels of the blood pressure drug were sky-high, long before the results came back. He felt very light-headed and then actually fainted. This was a very powerful indication that his blood pressure was much too low, thanks to high levels of the felodipine.

This was the very first recorded instance of a pharmacokinetic interaction between a citrus juice and a drug.

But it seems impossible. Grapefruit does not contain any felodipine. Your body does not make the drug felodipine. So where does the extra felodipine come from?

How Does It Work?

The mechanisms by which grapefruit juice increases the blood levels of certain drugs are complicated, and have taken many years to understand. In this case, grapefruit juice increased the oral absorption of the felodipine.

A rough analogy might be a stupid radio station promotion, in which a million dollars is dumped into a fast-flowing stream. You can keep all the money that you can scoop out of the

stream—but the radio station has given you only a tiny teaspoon to do the scooping. You could collect more banknotes if you used a butterfly net.

In a similar way, the medication enters at your mouth and leaves via the ‘other end’ into your toilet bowl. Only a small amount leaves your gut and enters your bloodstream. With some drugs, however, grapefruit juice increases how much gets absorbed (or ‘scooped’) into your bloodstream.

In other words, you swallow a certain dose of the drug (say, 5 mg). But only (say) 0.5 mg actually makes its way from the gut into the bloodstream. The remaining 4.5 mg goes out through the S-bend and into the sewer.

But with some drugs, the presence of grapefruit juice in the gut increases the quantity of drug that is absorbed into the bloodstream.

More Technical Explanation

Enzymes are chemicals that kick certain chemical reactions along.

Cells in the wall of the human gut – known as apical enterocytes – contain many, many enzymes. A specific subfamily of the cytochrome P450 enzymes is especially relevant, if you have grapefruit juice in your gut and take certain medications.

These cytochrome P450 enzymes normally break down, or metabolise, certain drugs such as nifedipine, felodipine, nimodipine, cyclosporin and midazolam. They might destroy over half of the drug while it’s in your gut. This means that under normal conditions, these cytochrome P450 enzymes lead to fairly low levels of these drugs being available for absorption into the bloodstream.

But grapefruit inhibits or reduces the activity of these destructive enzymes, so they work more slowly. The enzymes now don’t do a very good job of breaking down the drugs that you swallow. As a result, more of these drugs are available to be absorbed into the bloodstream.

If you really want more technical details, the specific subfamily is cytochrome P450 3A4 (CYP3A4). This means that grapefruit affects only those drugs that are metabolised by cytochrome P450 3A4 (CYP3A4). It turns out that in our society, the elderly are the ones most likely to take medications that are metabolised by cytochrome P450 3A4 (CYP3A4).

And if you want to get really technical, the active chemicals in the grapefruit that do the inhibiting are called ‘furanocoumarins’. There may be other chemicals that also do the inhibiting, but we haven’t discovered them yet.

Drugs Go Up

In addition to the blood pressure drugs in the felodipine group, grapefruit alters the natural absorption of many other drugs. In fact, when taking these medications, grapefruit juice can sometimes send a person’s blood levels of the drug dangerously high. These medications include some blood pressure drugs, antihistamines, hormones, immunosuppressives, antivirals, anticonvulsants, statins (for cholesterol), sedatives, opiates, antidepressants of the SSRI variety, and even Viagra (causing painful erection, low blood pressure and impaired vision).

And we have found other fruits (e.g. limes, Seville oranges and sometimes even apples) that can increase the levels of some drugs in your body.

However, just to show how complicated the body is, while double-strength grapefruit juice tripled the blood levels of felodipine, some varieties of orange juice had no effect at all.

We can’t really use this effect to reliably increase medication levels in people. One reason is that this effect is very strong in some people and very weak in others. Another reason is that grapefruit varies enormously in its strength, from one variety to the next, from one farm to the next, from one fruit juice manufacturer to the next, from one batch to the next, and so on.

Drugs Go Down

And, of course, because the human body is so complicated, drug levels in the blood can sometimes decrease when different drugs and fruit are mixed.

In August 2008 our hero, Dr David Bailey (now a Professor of Clinical Pharmacology), announced that all the aforementioned fruits (i.e. grapefruit, limes, Seville Oranges and apples) can sometimes decrease the blood levels of some other medications.

In this case, a different chemical in grapefruit works via a different pathway. The active ingredient is called ‘naringin’. It seems to block an important drug uptake transporter, called ‘OATP1A2’. This carries drugs from the small intestine to the bloodstream. So if you block this transporter, you reduce the quantity of medication that gets carried into the bloodstream.

Various drugs have their blood concentrations lowered if you take them with the juice of grapefruit, orange and apple. These drugs include etoposide (an anti-cancer drug), certain beta blockers used to treat high blood pressure and prevent heart attacks (such as atenolol, celipropol and talinolol), and some antibiotics (ciprofloxacin, levofloxacin and itraconazole).

In oranges, the active chemical that interferes with the transporter, OATP1A2, is ‘hesperidin’. But the active chemical in apples that does the interfering has not yet been identified.

What to Do?

Because this effect happens in the gut, it works only with medications that you swallow. Medications that are injected into the bloodstream or muscles bypass the gut, and are therefore not affected by any grapefruit in your diet.

The lesson here is to check with your doctor or pharmacist about possible interactions with your medications—including food. After all, many medications are taken at breakfast, and that’s when grapefruit juice might also be taken. The journal
Australian Adverse Drug Reactions Bulletin
advises, ‘Separate grapefruit juice and medication by a minimum of two hours.’