The bioavailability of intranasal and smoked methamphetamine

This might present a surprise or 2


The bioavailability of intranasal and smoked methamphetamine by Debra S. Harris, MD, Harold Boxenbaum, PhD, E. Thomas Everhart, PhD, Gina Sequeira, MS, John E. Mendelson, MD, and Reese T. Jones, MD San Francisco, Calif (Clin Pharmacol Ther 2003;74:475-86.)

Background:

Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally.

Methods:

Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods.

Results:

Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL /hour /kg), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL /hour /kg, respectively.

Conclusions:

Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

(Clin Pharmacol Ther 2003;74:475-86.)

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Full pdf here

[Colour added for emphasis; p_d]

P_D just wondering if you could explain to me (that is if you know) why the intravenous half life is longer than the other two routes of administration.

I would assume its both because of the way the drug is distributed as well as the accompanied small change in plasma pH.

Although the non-compartmental model was used in this study when examining bio-availability, the compartmental model of distribution would be expected increase the 1/2 life of most lipophilic or prontonatable drugs (e.g. primary & secondary amines) particularly when administered intravenously.

I know it's got something to do with blood, but what does plasma refer to in this context p_d?

For this example, consider it "the watery part of blood"

with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute

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Could someone please explain that too me, i dont understand what it is saying exactly. Is it saying that 79% is absorbed when admisistrated intranasaly, and 67% when smoked?

thanks in advance.

Sorry paca. A couple of minor characters didn't copy and paste properly. I've fixed up the missing bracket which should help to explain things.

It should now read that 79% was bio-available (absorbed) with insufflation.

The total amount absorbed from inhaled vapour equated to 37.4% of the amount in the pipe.

Thanks for that phase_dancer, very informative article. However, the statistics made me question my understanding of the term "elimination half life"...I've always taken that as the time it takes for the body to remove half the dosage, but 10 hours seems to be a little long to me.

eg insufflating 100 mg of meth would mean 50 mg is still available 10 hours later and 25 mg 20 hours after the dose.
(math using 100% bioavailability instead of 79% so calculators would not be required)

It doesn't seem right, or have I misunderstood something? Is half life always linear?

I understand that some benzos eg clonazepam may have a relatively long half life, but you just don't "feel" it after a while so continuous dosing needs to be done to acheive a steady concentration. However, 25 mg still is at the threshold level so theoretically, 20 hours after the first dose (not taking into consideration multiple doses, complicates calculations, my math is bad) the person would still be able to "feel" it, which doesn't seem to hold true in practise?

The most puzzling number is the maximum concentrations time though. I can understand this from the analogy with benzos, eg the peak plasma concentration (which I assume is the same as maximum concentration) is right as in you feel the maximum effects at that point.

I'll be surprised if people feel the maximum effects of meth 2+ hours past the dose...I was under the impression that the peak effects occur not long after dosing, and decreases in intensity from there.

I'll appreciate it if someone can clear this up, it's a little confusing. Thanks!

The compartmental model of drug distribution is important to grasp if an understanding of drug kinetics is sought. I won't attempt this today, but it's becoming obvious that a thorough explanation with pictures is required.

In the meantime, lets look at some of the chemical and pharmacological properties of Meth which make it a stable molecule with a long elimination half life. I'll also attempt to address sixthseal's point mentioned; that it seems as though more than half is gone after a few hours, as effect is considerably less than that experienced when meth was first administered.



Metabolism

Meth and Amphetamine both have relatively long half lives, but meth is far greater (12-17 hours normally) and both have longer 1/2 lives than MDMA.

Why?

Non-ring substituted amphetamines have a single alkyl chain coming off a benzene ring. There are no chemical "handles" sticking off the ring, making it unaffected by enzymes which "grab" or bind/bond onto these attached chemical groups. Meth also differs chemically from amphetamine in that a methyl group exists on the nitrogen of the amine. Meth is usually metabolised initially (First Pass) by either;

• Demethylation - (removing the methyl group of the amine on meth)
• p-Hydroxylation (attaching a OH- group to the 4th position (para) on the ring (NB;the alkyl chain attaches at the 1st position)
• Oxidation - amphetamine (attaching an OH- group to either 1st carbon on alkyl chain, or further oxidising to produce the ketone

Fig. 1 : Metabolism of Amphetamines





Fig. 2 : Metabolism of Methamphetamines







Taken from: Here

Besides elimination of the various metabolites, both meth and amphetamine are also eliminated unchanged in the urine. In addition to the stable properties of the molecules, another part of this reason lies in the ability for both amphetamine and meth to be protonated in an acid environment. Amphetamines are described as being weak bases. As the body is mostly acidic, this in itself aids with elimination. But there is a limit to how much will be excreted via endogenous protonation. Making the urine more acidic will "retain" more molecules when passing through the convoluted tubules of the kidneys, and therefore hasten elimination.

Much of the amphetamines not eliminated via this route, will continue to circulate, attempting to "do their business", until metabolised into less active and/or to inactive products. These molecules are usually more easily eliminated.


Receptor Actions

Amphetamine works primarily by being taken up into pre-synaptic neurons. The order of potency on the major affected receptors is:

NE > DA and >> 5HT (predominately NE but to a small degree 5HT also).

These neurons have reserves of the neurotransmitters, which are released in relatively large amounts due to actions of amphetamine mimicking endogenous ligands. Amp/Meth also slightly knocks out MAO-B, which is the principle means these cells use to regulate any "normal" upsets in free levels of these chemicals. Levels of extracellular DA and NE, pumped out by the actions of the drug, rise until reserves are depleted. Although at this stage the body has already begun to respond, by producing more of these neurotransmitters, the process is not instant, and as we know it can take several days to completely replenish reserves of DA & NE (weeks in the case of 5HT).

Dopamine/ NA carrier molecules and associated processes involved in delivering the drug are also inhibited and depleted. Although directly affected by Amp/Meth, this process is quite possibly also a protection mechanism to avoid over stimulation of receptors.

Receptors themselves also "shy away" by receding into pits created within the cell membrane where the receptors lie. These effectively shield the receptors, preventing un-metabolised Amp/meth from reaching it's targets.

Larger doses may overcome some of these tolerance based reduction in actions, by simply forcing the final reserves of these neurotransmitters to accumulate in the cytosol of the cell. Beyond a certain point, the drug has little affect other than prolonging replenishment. Crash phase becoming inevitable.....


Summary of key Points


Half life extended by the resilience of the molecule to enzyme attack ( and drug distribution characteristics -not discussed)

Bio-response limited by the availability and stores of neurotransmitters

Receptor responses limiting binding and secondary effects.

Thanks for the reply phase_dancer. The bit about receptors "shying away" is an intriguing concept. The idea is strangely disturbing for some reason...

^^ Regarding receptor sequestration; you'll find it explained better with pictures here. Some good links also.

smoke or...

..*bump*

Interesting stuff. I think I'll still avoid snorting it though.

The below reference is the only paper I can find which looks at the pharmacokinetics of ORAL methamphetamine. I'm just wondering how those bioavailabilities compare to oral use. The below paper doesn't comment on the bioavailability, at least in the abstract, I imagine because it is a bitch to figure out, unless we assume the volume of distribution is the same in IV and oral use....

C.E. Cook, A.R. Jeffcoat, B.M. Sadler, J.M. Hill, R.D. Voyksner, D.E. Pugh et al., Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans. Drug Metab Dispos 20 (1992), pp. 856–862

Thanks for the post p_d, your posts always leave my head hurting but I learn heaps! Thanks again.

Just a question, why does the levels peak about 2.5 hours after administration?

^^ Pharmacokinetics, or more specifically; drug absorption, distribution, saturation, redistribution and elimination.

When I've time I'll attempt to address this topic in some detail (unless someone else would like to). But as BilZ0r indicated, there's no easy way round the math with complicated multiple compartment models of distribution, redistribution, clearance etc.

So Pharmacologists usually limit this to 2;

A central compartment by which all of the drug must pass through during distribution, redistribution and elimination. This usually represents blood plasma and sometimes other non-vascular areas

and

A second compartment termed the peripheral compartment which represents all other tissues.

However, as each type of tissue can have different characteristics in regards to lipid soluble drugs, more complex models are needed with these substances. Even then you only get approximations, and the result only produces a time course of plasma levels and not a steady state figure

Hope that makes sense...

makes sense to me.....even though i only skimmed through those big words.

no wonder i didnt get half as buzzy from smoking as i do from railing it.

P_D I think I understand. So you mean it's like the meth has turned up to the club, but is waiting in the queue for 2.4 hours before it can get in a party.

It's a bit more like; all the "meth" is initially spread throughout the club before eventually all coming together in the main room for the big set!