DCHAS-L Archives Jun 13 2010 - Re: toxicity question

--0-274010685-1276494005=:89364 Hi Nick, =C2=A0 While Alan declined commenting on the dosing question, my experience in pot ency testing of pharmaceuticals leads me to say - Yes, the form of the salt plays an important part in several ways. =C2=A0 Assuming the Active Ingredient is in fact just half of=C2=A0an ionic pair, =C2=A0 you have to look at the % composition based on the ion vs the entire molecule.=C2=A0Secondly, the chosen ionic pair will have an effect on the uptake of the Active Ingredient due to solubility, how easily it is absorbe d through the skin, intestines, et al.=C2=A0 =C2=A0 When you get to the case of larger organic molecules i.e.ligands, macrocycl es, and such, considerations like how they bind to metals (preferentially o r not, and to which=C2=A0metals)can make a difference in how they=C2=A0beha ve chemically.=C2=A0 =C2=A0 With the wide array of talents assembled here, I'm probably too vague for s ome, too pedantic for others, and preaching to the choir for yet another gr oup.=C2=A0 Suffice it to say in summary that I am convinced that the choice of salt composition can make a huge difference in dosing, uptake, and effe ctiveness/efficacy. Todd Perkins --- On Fri, 6/11/10, Tsiakals, Nicholas John wrote: From: Tsiakals, Nicholas John Subject: Re: [DCHAS-L] toxicity question To: DCHAS-L**At_Symbol_Here**LIST.UVM.EDU Date: Friday, June 11, 2010, 4:45 PM Sounds like you=E2=80=99re saying that comparing the solubility of one salt to another plays a part in that overall dosing question. =C2=A0 That helps, Alan.=C2=A0 Thanks! =C2=A0 -Nick =C2=A0 From: DCHAS-L Discussion List [mailto:DCHAS-L**At_Symbol_Here**LIST.UVM.EDU] On Behalf Of Al an Hall Sent: Friday, June 11, 2010 9:41 AM To: DCHAS-L**At_Symbol_Here**LIST.UVM.EDU Subject: Re: [DCHAS-L] toxicity question =C2=A0 Nick et al, =C2=A0 In general, the toxicity would not change with the=C2=A0salt involved, alth ough there are exceptions.=C2=A0 For example, when treating hydrofluoric ac id (HF) exposures with calcium salts, the calcium gluconate salt can be use d topically, injected intradermally, or given intravenously or interarteria lly.=C2=A0 However, the calcium chloride salt can only be injected intraven ously, because it causes severe skin damage and sloughing if extravasated f rom a vein or injected intradermally and can cause devastating vascular inj ury if injected intraarterially.=C2=A0=C2=A0 =C2=A0 Calcium salts are also a good example of the second point.=C2=A0 The dose o f the active ingredient can vary significantly with the same volume of diff erent salts.=C2=A0 In the calcium example, the calcium chloride salt=C2=A0i n a given volume will have approximately 3 times more Ca+2 ion that the sam e volume of the calcium gluconate salt.=C2=A0 When treating life-threatenin g cardiovascular complications of hydrofluoric acid systemic toxicity, it i s therefore often wise to choose the calcium chloride salt for intravenous infusion (with precautions against extravaasation), as a much higher dose o f calcium ion can provided with the same volume and the same infusion time. =C2=A0 A similar comparison might be made for norepinephrine, but what the relatio nship of dose is between various salt forms in the same volume, I don't hav e memorized. =C2=A0 Hope this answers the question. =C2=A0 Alan Alan H. Hall, M.D. President and=C2=A0Chief Medical Toxicologist Toxicology Consulting and Medical Translating Services, Inc. Laramie, WY =C2=A0 Clinical Assistant Professor Colorado School of Public Health Denver, CO =C2=A0 > Date: Thu, 10 Jun 2010 16:30:45 -0500 > From: tsiakals**At_Symbol_Here**ILLINOIS.EDU > Subject: [DCHAS-L] toxicity question > To: DCHAS-L**At_Symbol_Here**LIST.UVM.EDU > > Good afternoon all, > > How does toxicity compare from one pharmaceutical salt to another? More s pecifically, is the toxicity of norepinephrine the same as norepinephrine b itartrate salt? > > Thanks, > -Nick --0-274010685-1276494005=:89364

Hi Nick,

While Alan declined commenting on the dosing question, my experience i n potency testing of pharmaceuticals leads me to say - Yes, the form of the salt plays an important part in several ways.

Assuming the Active Ingredient is in fact just half of an ionic p air, you have to look at the % composition based on the ion vs the en tire molecule. Secondly, the chosen ionic pair will have an effect on the uptake of the Active Ingredient due to solubility, how easily it is abs orbed through the skin, intestines, et al.

When you get to the case of larger organic molecules i.e.ligands, macr ocycles, and such, considerations like how they bind to metals (preferentia lly or not, and to which metals)can make a difference in how they ;behave chemically.

With the wide array of talents assembled here, I'm probably too vague for some, too pedantic for others, and preaching to the choir for yet anoth er group. Suffice it to say in summary that I am convinced that the c hoice of salt composition can make a huge difference in dosing, uptake, and effectiveness/efficacy.

Todd Perkins

--- On Fri, 6/11/10, Tsiakals, Nicholas John <tsiakals**At_Symbol_Here**IL LINOIS.EDU> wrote:

From: Tsiakals, Nicholas John <tsiakals**At_Symbol_Here**ILLINO IS.EDU>
Subject: Re: [DCHAS-L] toxicity question
To: DCHAS-L**At_Symbol_Here**LIST. UVM.EDU
Date: Friday, June 11, 2010, 4:45 PM

Sounds like you=E2=80=99re saying that comparing the s olubility of one salt to another plays a part in that overall dosing questi on.

That helps, Alan. Thanks!

-Nick

From: DCHAS-L Discussion List [mailto:DCHAS-L**At_Symbol_Here**LIST.UVM.EDU] On Behalf Of Alan Hall
Sent: Friday, June 11, 2010 9:41 AM
To: DCHAS-L**At_Symbol_Here**LIST.UVM.EDU
Subject: Re: [DCHAS-L] toxicity question< /SPAN>

Nick et al,

In general, the toxicity would not change wit h the salt involved, although there are exceptions. For example, when treating hydrofluoric acid (HF) exposures with calcium salts, the cal cium gluconate salt can be used topically, injected intradermally, or given intravenously or interarterially. However, the calcium chloride salt can only be injected intravenously, because it causes severe skin damage a nd sloughing if extravasated from a vein or injected intradermally and can cause devastating vascular injury if injected intraarterially. < BR>
Calcium salts are also a good example of the second point. The dose of the active ingredient can vary significantly with the same v olume of different salts. In the calcium example, the calcium chlorid e salt in a given volume will have approximately 3 times more Ca+2 ion that the same volume of the calcium gluconate salt. When treatin g life-threatening cardiovascular complications of hydrofluoric acid system ic toxicity, it is therefore often wise to choose the calcium chloride salt for intravenous infusion (with precautions against extravaasation), as a m uch higher dose of calcium ion can provided with the same volume and the sa me infusion time.

A similar comparison might be made for norep inephrine, but what the relationship of dose is between various salt forms in the same volume, I don't have memorized.

Hope this answers the question.

Alan
Alan H. Hall, M.D.
President and ;Chief Medical Toxicologist
Toxicology Consulting and Medical Translatin g Services, Inc.
Laramie, WY

Clinical Assistant ProfessorColorado School of Public Health
Denver, CO

> Date: Th u, 10 Jun 2010 16:30:45 -0500
> From: tsiakals**At_Symbol_Here**ILLINOIS.EDU
> Subject: [DCHAS-L] toxicity question
> To: DCHAS-L**At_Symbol_Here**LIST.UVM.EDU
>
> Good afternoon all,
>
> How does toxicity compare from one pharmaceutical salt to another? Mor e specifically, is the toxicity of norepinephrine the same as norepinephrin e bitartrate salt?
>
> Thanks,
> -Nick
--0-274010685-1276494005=:89364--

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